Genetic polymorphisms associated with cardiovascular diseases, methods of detection and uses thereof

ABSTRACT

The present invention provides compositions and methods based on genetic polymorphisms that are associated with cardiovascular diseases, particularly coronary heart disease (especially myocardial infarction) or hypertension. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. non-provisionalapplication Ser. No. 12/500,378, filed on Jul. 9, 2009, which claimspriority to U.S. provisional application Ser. No. 61/134,522, filed onJul. 9, 2008, the contents of each of which are hereby incorporated byreference in their entirety into this application.

FIELD OF THE INVENTION

The present invention is in the field of cardiovascular diseases (CVD),particularly coronary heart disease (CHD), including myocardialinfarction (MI), and hypertension. In particular, the present inventionrelates to specific single nucleotide polymorphisms (SNPs) in the humangenome, and their association with CVD. The SNPs disclosed herein can beused as targets for the design of diagnostic reagents and thedevelopment of therapeutic agents, as well as for disease associationand linkage analysis. In particular, the SNPs of the present inventionare useful for such uses as identifying an individual who has anincreased or decreased risk of developing CVD (particularly CHD, such asMI, and hypertension), for early detection of the disease, for providingclinically important information for the prevention and/or treatment ofCVD, for predicting progression or recurrence of CVD, for predicting theseriousness or consequences of CVD in an individual, for determining theprognosis of an individual's recovery from CVD, for screening andselecting therapeutic agents, and for predicting a patient's response totherapeutic agents such as evaluating the likelihood of an individualresponding positively to a therapeutic agent such as a statin,particularly for the treatment or prevention of CVD (such as CHD,particularly MI, and hypertension). The SNPs disclosed herein are alsouseful for human identification applications.

Methods, assays, kits, and reagents for detecting the presence of thesepolymorphisms and their encoded products are provided.

BACKGROUND OF THE INVENTION

Cardiovascular Diseases (CVD)

Cardiovascular diseases (CVD) include, for example, coronary heartdisease (CHD) and hypertension. CHD includes, for example, myocardialinfarction (MI).

Coronary Heart Disease (CHD), including Myocardial Infarction (MI)

The present invention relates to SNPs that are associated with theoccurrence of coronary heart disease (CHD), particularly myocardialinfarction (MI).

CHD is defined in the Framingham Heart Study as encompassing MI, anginapectoris, coronary insufficiency (which is manifested as ischemia, thatis, impaired oxygen flow to the heart muscle), and coronary heartdisease death (Wilson et al., Circulation 97:1837-1847 (1998)). CHD maybe recorded through clinical records that indicate the followinginterventions: coronary artery bypass graft (CABG), angioplasty (e.g.,percutaneous transluminal coronary angioplasty (PTCA)), andrevascularization (stent placement), in addition to clinical records ofMI, angina, or coronary death.

As used herein, CHD is defined in accordance with how this term isdefined in the Framingham Heart Study (i.e., as encompassing MI, anginapectoris, coronary insufficiency, and coronary heart disease death).Angina pectoris includes unstable angina in particular. The SNPsdescribed herein may further be useful for such cardiovascular events asvulnerable plaque and stroke.

Myocardial Infarction (MI)

Myocardial infarction (MI), also referred to as a “heart attack”, is themost common cause of mortality in developed countries. The incidence ofMI is still high despite currently available preventive measures andtherapeutic intervention. More than 1,500,000 people in the U.S. sufferacute MI each year, many without seeking help due to unrecognized MI,and one third of these people die. The lifetime risk of coronary arterydisease events at age 40 is 42.4% for men, nearly one in two, and 24.9%for women, or one in four. D. M. Lloyd-Jones, Lancet 353:89-92 (1999).

MI is a multifactorial disease that involves atherogenesis, thrombusformation and propagation. Thrombosis can result in complete or partialocclusion of coronary arteries. The luminal narrowing or blockage ofcoronary arteries reduces oxygen and nutrient supply to the cardiacmuscle (cardiac ischemia), leading to myocardial necrosis and/orstunning. MI, unstable angina, and sudden ischemic death are clinicalmanifestations of cardiac muscle damage. All three endpoints are part ofacute coronary syndrome since the underlying mechanisms of acutecomplications of atherosclerosis are considered to be the same.

Atherogenesis, the first step of pathogenesis of MI, is a complexinteraction between blood elements, mechanical forces, disturbed bloodflow, and vessel wall abnormality that results in plaque accumulation.An unstable (vulnerable) plaque was recognized as an underlying cause ofarterial thrombotic events and MI. A vulnerable plaque is a plaque,often not stenotic, that has a high likelihood of becoming disrupted oreroded, thus forming a thrombogenic focus. MI due to a vulnerable plaqueis a complex phenomenon that includes: plaque vulnerability, bloodvulnerability (hypercoagulation, hypothrombolysis), and heartvulnerability (sensitivity of the heart to ischemia or propensity forarrhythmia). Recurrent myocardial infarction (RMI) can generally beviewed as a severe form of MI progression caused by multiple vulnerableplaques that are able to undergo pre-rupture or a pre-erosive state,coupled with extreme blood coagulability.

The current diagnosis of MI is based on the levels of troponin I or Tthat indicate the cardiac muscle progressive necrosis, impairedelectrocardiogram (ECG), and detection of abnormal ventricular wallmotion or angiographic data (the presence of acute thrombi). However,due to the asymptomatic nature of 25% of acute MIs (absence of atypicalchest pain, low ECG sensitivity), a significant portion of MIs are notdiagnosed and therefore not treated appropriately (e.g., prevention ofrecurrent MIs).

MI risk assessment and prognosis is currently done using classic riskfactors or the recently introduced Framingham Risk Index. Both of theseassessments put a significant weight on LDL levels to justify preventivetreatment. However, it is well established that half of all MIs occur inindividuals without overt hyperlipidemia.

Other emerging risk factors of MI are inflammatory biomarkers such asC-reactive protein (CRP), ICAM-1, SAA, TNF α, homocysteine, impairedfasting glucose, new lipid markers (ox LDL, Lp-a, MAD-LDL, etc.) andpro-thrombotic factors (fibrinogen, PAI-1). These markers havesignificant limitations such as low specificity and low positivepredictive value, and the need for multiple reference intervals to beused for different groups of people (e.g., males-females, smokers-nonsmokers, hormone replacement therapy users, different age groups). Theselimitations diminish the utility of such markers as independentprognostic markers for MI screening.

Genetics plays an important role in MI risk. Families with a positivefamily history of MI account for 14% of the general population, 72% ofpremature MIs, and 48% of all MIs. R. R. Williams, Am J Cardiology87:129 (2001). In addition, replicated linkage studies have revealedevidence of multiple regions of the genome that are associated with MIand relevant to MI genetic traits, including regions on chromosomes 14,2, 3 and 7, implying that genetic risk factors influence the onset,manifestation, and progression of MI. U. Broeckel, Nature Genetics30:210 (2002); S. Harrap, Arterioscler Thromb Vasc Biol 22:874-878(2002); A. Shearman, Human Molecular Genetics 9:1315-1320 (2000). Recentassociation studies have identified allelic variants that are associatedwith acute complications of CHD, including allelic variants of the ApoE,ApoA5, Lpa, APOCIII, and Klotho genes.

Genetic markers such as single nucleotide polymorphisms (SNPs) arepreferable to other types of biomarkers. Genetic markers that areprognostic for MI can be genotyped early in life and could predictindividual response to various risk factors. The combination of serumprotein levels and genetic predisposition revealed by genetic analysisof susceptibility genes can provide an integrated assessment of theinteraction between genotypes and environmental factors, resulting insynergistically increased prognostic value of diagnostic tests.

Thus, there is an urgent need for novel genetic markers that arepredictive of predisposition to CHD such as MI, particularly forindividuals who are unrecognized as having a predisposition to MI. Suchgenetic markers may enable prognosis of MI in much larger populationscompared with the populations that can currently be evaluated by usingexisting risk factors and biomarkers. The availability of a genetic testmay allow, for example, appropriate preventive treatments for acutecoronary events to be provided for susceptible individuals (suchpreventive treatments may include, for example, statin treatments andstatin dose escalation, as well as changes to modifiable risk factors),lowering of the thresholds for ECG and angiography testing, and allowadequate monitoring of informative biomarkers. Moreover, the discoveryof genetic markers associated with MI will provide novel targets fortherapeutic intervention or preventive treatments of MI, and enable thedevelopment of new therapeutic agents for treating or preventing MI andother cardiovascular disorders.

Furthermore, novel genetic markers that are predictive of predispositionto MI can be particularly useful for identifying individuals who are atrisk for early-onset MI. “Early-onset MI” may be defined as MI in menwho are less than 55 years of age and women who are less than 65 yearsof age. K. O. Akosah et al., “Preventing myocardial infarction in theyoung adult in the first place: How do the National CholesterolEducation Panel III guidelines perform?” JACC 41(9):1475-1479 (2003).Individuals who experience early-onset MI may not be effectivelyidentified by current cholesterol treatment guidelines, such as thosesuggested by the National Cholesterol Education Program. In one study,for example, a significant number of individuals who suffered MI at anearlier age (≦50 years) were shown to have LDL cholesterol below 100mg/dl. K. O. Akosah et al., “Myocardial infarction in young adults withlow-density lipoprotein cholesterol levels less than or equal to 100mg/dl. Clinical profile and 1-year outcomes.” Chest 120:1953-1958(2001). Because risk for MI can be reduced by lifestyle changes and bytreatment of modifiable risk factors, better methods to identifyindividuals at risk for early-onset MI could be useful for makingpreventive treatment decisions, especially considering that thesepatients may not be identified for medical management by conventionaltreatment guidelines. Genetic markers for risk of early-onset MI couldpotentially be incorporated into individual risk assessment protocols,as they have the advantage of being easily detected at any age.

Hypertension

Hypertension is a significant, modifiable risk factor for both CHD andstroke; two of the top three causes of mortality in the United States(Kearney et al., Lancet. 2005; 365:217-223; and Centers for DiseaseControl and Prevention, National Center for Health Statistics,FastStats). The prevalence of hypertension in US adults is estimated tobe 29% (Ostchega et al., 2008, National Center for Health Statisticsdata brief no. 3), and the prevalence is expected to increase in thefuture (Kearney et al., Lancet. 2005; 365:217-223; and Hajjar et al.,JAMA. 2003; 290:199-206). While about 5% of hypertension has knowncauses (classified as secondary hypertension), the majority ofhypertension is due to unknown causes (classified as essentialhypertension) (Cowley et al., Nature Reviews Genetics. 2006; 7:829-840).It is estimated that genetic variation contributes to between 30-60% ofinter-individual blood pressure variation (Binder, Curr Opin Cardiol.2007; 22:176-184) but the identity and nature of the contributinggenetic loci are largely unknown.

Statin Treatment

HMG-CoA reductase inhibitors (statins) are used for the treatment andprevention of CVD, particularly MI. Reduction of MI and other coronaryevents and total mortality by treatment with HMG-CoA reductaseinhibitors has been demonstrated in a number of randomized,double-blinded, placebo-controlled prospective trials. D. D. Waters,Clin Cardiol 24(8 Suppl):1113-7 (2001); B. K. Singh and J. L. Mehta,Curr Opin Cardiol 17(5):503-11 (2002). These drugs have their primaryeffect through the inhibition of hepatic cholesterol synthesis, therebyupregulating LDL receptors in the liver. The resultant increase in LDLcatabolism results in decreased circulating LDL, a major risk factor forcardiovascular disease.

Statins can be divided into two types according to their physicochemicaland pharmacokinetic properties. Statins such as lovastatin, simvastatin,atorvastatin, and cerevastatin are lipophilic in nature and, as such,diffuse across membranes and thus are highly cell permeable. Hydrophilicstatins such as pravastatin are more polar, such that they requirespecific cell surface transporters for cellular uptake. K. Ziegler andW. Stunkel, Biochim Biophys Acta 1139(3):203-9 (1992); M. Yamazaki etal., Am J Physiol 264(1 Pt 1):G36-44 (1993); T. Komai et al., BiochemPharmacol 43(4):667-70 (1992). The latter statin utilizes a transporter,OATP2, whose tissue distribution is confined to the liver and,therefore, they are relatively hepato-specific inhibitors. B. Hsiang etal., J Biol Chem 274(52):37161-37168 (1999). The former statins, notrequiring specific transport mechanisms, are available to all cells andthey can directly impact a much broader spectrum of cells and tissues.These differences in properties may influence the spectrum of activitiesthat each statin possesses. Pravastatin, for instance, has a lowmyopathic potential in animal models and myocyte cultures compared tolipophilic statins. B. A. Masters et al., Toxicol Appl Pharmacol131(1):163-174 (1995); K. Nakahara et al., Toxicol Appl Pharmacol152(1):99-106 (1998); J. C. Reijneveld et al., Pediatr Res39(6):1028-1035 (1996).

Evidence from gene association studies is accumulating to indicate thatresponses to drugs are, indeed, at least partly under genetic control.As such, pharmacogenetics—the study of variability in drug responsesattributed to hereditary factors in different populations—maysignificantly assist in providing answers toward meeting this challenge.A. D. Roses, Nature 405(6788):857-865 (2000); V. Mooser et al., J ThrombHaemost 1(7):1398-1402 (2003); L. M. Humma and S. G. Terra, Am J HealthSyst Pharm 59(13):1241-1252 (2002). Numerous associations have beenreported between selected genotypes, as defined by SNPs and othergenetic sequence variations, and specific responses to cardiovasculardrugs. Polymorphisms in several genes have been suggested to influenceresponses to statins including CETP (J. A. Kuivenhoven et al., N Engl JMed 338(2):86-93 (1998)), beta-fibrinogen (M. P. de Maat et al.,Arterioscler Thromb Vasc Biol 18(2):265-71 (1998)), hepatic lipase (A.Zambon et al., Circulation 103(6):792-798 (2001)), lipoprotein lipase(J. W. Jukema et al., Circulation 94(8):1913-1918 (1996)), glycoproteinIIIc (P. F. Bray et al., Am J Cardiol 88(4):347-352 (2001)),stromelysin-1 (M. P. de Maat et al., Am J Cardiol 83(6):852-856 (1999)),and apolipoprotein E (L. U. Gerdes et al., Circulation 101(12):1366-1371(2000); J. Pedro-Botet et al., Atherosclerosis 158(1):183-193 (2001)).Some of these variants were shown to effect clinical events while otherswere associated with changes in surrogate endpoints.

Thus, there is a need for genetic markers that can be used to predict anindividual's responsiveness to statins. For example, there is a growingneed to better identify people who have the highest chance of benefitingfrom statins, and those who have the lowest risk of developingside-effects. For example, severe myopathies represent a significantrisk for a low percentage of the patient population, and this may be aparticular concern for patients who are treated more aggressively withstatins.

Single Nucleotide Polymorphisms (SNPs)

The genomes of all organisms undergo spontaneous mutation in the courseof their continuing evolution, generating variant forms of progenitorgenetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variantform may confer an evolutionary advantage or disadvantage relative to aprogenitor form or may be neutral. In some instances, a variant formconfers an evolutionary advantage to the species and is eventuallyincorporated into the DNA of many or most members of the species andeffectively becomes the progenitor form. Additionally, the effects of avariant form may be both beneficial and detrimental, depending on thecircumstances. For example, a heterozygous sickle cell mutation confersresistance to malaria, but a homozygous sickle cell mutation is usuallylethal. In many cases, both progenitor and variant forms survive andco-exist in a species population. The coexistence of multiple forms of agenetic sequence gives rise to genetic polymorphisms, including SNPs.

Approximately 90% of all genetic polymorphisms in the human genome areSNPs. SNPs are single base positions in DNA at which different alleles,or alternative nucleotides, exist in a population. The SNP position(interchangeably referred to herein as SNP, SNP site, SNP locus, SNPmarker, or marker) is usually preceded by and followed by highlyconserved sequences of the allele (e.g., sequences that vary in lessthan 1/100 or 1/1000 members of the populations). An individual may behomozygous or heterozygous for an allele at each SNP position. A SNPcan, in some instances, be referred to as a “cSNP” to denote that thenucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at thepolymorphic site. Substitutions can be transitions or transversions. Atransition is the replacement of one purine nucleotide by another purinenucleotide, or one pyrimidine by another pyrimidine. A transversion isthe replacement of a purine by a pyrimidine, or vice versa. A SNP mayalso be a single base insertion or deletion variant referred to as an“indel.” Weber et al., “Human diallelic insertion/deletionpolymorphisms,” Am J Hum Genet. 71(4):854-62 (October 2002).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP,”“polymorphism,” “mutation,” “mutant,” “variation,” and “variant” areused herein interchangeably), is one that does not result in a change ofamino acid due to the degeneracy of the genetic code. A substitutionthat changes a codon coding for one amino acid to a codon coding for adifferent amino acid (i.e., a non-synonymous codon change) is referredto as a missense mutation. A nonsense mutation results in a type ofnon-synonymous codon change in which a stop codon is formed, therebyleading to premature termination of a polypeptide chain and a truncatedprotein. A read-through mutation is another type of non-synonymous codonchange that causes the destruction of a stop codon, thereby resulting inan extended polypeptide product. While SNPs can be bi-, tri-, ortetra-allelic, the vast majority of the SNPs are bi-allelic, and arethus often referred to as “bi-allelic markers,” or “di-allelic markers.”

As used herein, references to SNPs and SNP genotypes include individualSNPs and/or haplotypes, which are groups of SNPs that are generallyinherited together. Haplotypes can have stronger correlations withdiseases or other phenotypic effects compared with individual SNPs, andtherefore may provide increased diagnostic accuracy in some cases.Stephens et al., Science 293:489-493 (July 2001).

Causative SNPs are those SNPs that produce alterations in geneexpression or in the expression, structure, and/or function of a geneproduct, and therefore are most predictive of a possible clinicalphenotype. One such class includes SNPs falling within regions of genesencoding a polypeptide product, i.e. cSNPs. These SNPs may result in analteration of the amino acid sequence of the polypeptide product (i.e.,non-synonymous codon changes) and give rise to the expression of adefective or other variant protein. Furthermore, in the case of nonsensemutations, a SNP may lead to premature termination of a polypeptideproduct. Such variant products can result in a pathological condition,e.g., genetic disease. Examples of genes in which a SNP within a codingsequence causes a genetic disease include sickle cell anemia and cysticfibrosis.

Causative SNPs do not necessarily have to occur in coding regions;causative SNPs can occur in, for example, any genetic region that canultimately affect the expression, structure, and/or activity of theprotein encoded by a nucleic acid. Such genetic regions include, forexample, those involved in transcription, such as SNPs in transcriptionfactor binding domains, SNPs in promoter regions, in areas involved intranscript processing, such as SNPs at intron-exon boundaries that maycause defective splicing, or SNPs in mRNA processing signal sequencessuch as polyadenylation signal regions. Some SNPs that are not causativeSNPs nevertheless are in close association with, and therefore segregatewith, a disease-causing sequence. In this situation, the presence of aSNP correlates with the presence of, or predisposition to, or anincreased risk in developing the disease. These SNPs, although notcausative, are nonetheless also useful for diagnostics, diseasepredisposition screening, and other uses.

An association study of a SNP and a specific disorder involvesdetermining the presence or frequency of the SNP allele in biologicalsamples from individuals with the disorder of interest, such as CVD, andcomparing the information to that of controls (i.e., individuals who donot have the disorder; controls may be also referred to as “healthy” or“normal” individuals) who are preferably of similar age and race. Theappropriate selection of patients and controls is important to thesuccess of SNP association studies. Therefore, a pool of individualswith well-characterized phenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biologicalsample obtained from a diseased individual, and compared to controlsamples, and selected for its increased (or decreased) occurrence in aspecific pathological condition, such as pathologies related to CVD andin particular, CHD (particularly MI) and hypertension. Once astatistically significant association is established between one or moreSNP(s) and a pathological condition (or other phenotype) of interest,then the region around the SNP can optionally be thoroughly screened toidentify the causative genetic locus/sequence(s) (e.g., causativeSNP/mutation, gene, regulatory region, etc.) that influences thepathological condition or phenotype. Association studies may beconducted within the general population and are not limited to studiesperformed on related individuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment withpharmaceuticals is often heterogeneous. There is a continuing need toimprove pharmaceutical agent design and therapy. In that regard, SNPscan be used to identify patients most suited to therapy with particularpharmaceutical agents (this is often termed “pharmacogenomics”).Similarly, SNPs can be used to exclude patients from certain treatmentdue to the patient's increased likelihood of developing toxic sideeffects or their likelihood of not responding to the treatment.Pharmacogenomics can also be used in pharmaceutical research to assistthe drug development and selection process. Linder et al., ClinicalChemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997);International Patent Application WO 97/40462, Spectra Biomedical; andSchafer et al., Nature Biotechnology 16:3 (1998).

SUMMARY OF THE INVENTION

The present invention relates to the identification of SNPs, as well asunique combinations of such SNPs and haplotypes of SNPs, that areassociated with cardiovascular diseases (CVD), particularly coronaryheart disease (CHD), especially myocardial infarction (MI), andhypertension. The polymorphisms disclosed herein are directly useful astargets for the design of diagnostic and prognostic reagents and thedevelopment of therapeutic and preventive agents for use in thediagnosis, prognosis, treatment, and/or prevention of CVD (particularlyCHD, such as MI, and hypertension).

Based on the identification of SNPs associated with CVD (particularlyCHD, especially MI, and hypertension), the present invention alsoprovides methods of detecting these variants as well as the design andpreparation of detection reagents needed to accomplish this task. Theinvention specifically provides, for example, SNPs associated with CVD,isolated nucleic acid molecules (including DNA and RNA molecules)containing these SNPs, variant proteins encoded by nucleic acidmolecules containing such SNPs, antibodies to the encoded variantproteins, computer-based and data storage systems containing the novelSNP information, methods of detecting these SNPs in a test sample,methods of identifying individuals who have an altered (i.e., increasedor decreased) risk of developing CVD (particularly CHD, such as MI, andhypertension), methods for determining the risk of an individual forrecurring CVD (e.g., recurrent CHD, particularly recurrent MI, orrecurrent hypertension), methods for prognosing the severity orconsequences of CVD, methods of treating an individual who has anincreased risk for CVD, and methods for identifying individuals (e.g.,determining a particular individual's likelihood) who have an altered(i.e., increased or decreased) likelihood of responding to a drugtreatment, particularly drug treatment of CVD (e.g., treatment orprevention of CHD, such as MI, or hypertension), based on the presenceor absence of one or more particular nucleotides (alleles) at one ormore SNP sites disclosed herein or the detection of one or more encodedvariant products (e.g., variant mRNA transcripts or variant proteins),methods of identifying individuals who are more or less likely torespond to a treatment such as statin treatment (or more or less likelyto experience undesirable side effects from a treatment), methods ofscreening for compounds useful in the treatment or prevention of adisorder associated with a variant gene/protein, compounds identified bythese methods, methods of treating or preventing disorders mediated by avariant gene/protein, methods of using the novel SNPs of the presentinvention for human identification, etc.

The present invention further provides methods for selecting orformulating a treatment regimen (e.g., methods for determining whetheror not to administer a treatment such as a statin to an individualhaving CVD, or who is at risk for developing CVD in the future, or whohas previously had CVD, methods for selecting a particular treatmentregimen such as dosage and frequency of administration of a therapeuticagent such as a statin, or a particular form/type of a therapeutic agentsuch as a particular pharmaceutical formulation or compound, etc.), andmethods for determining the likelihood of experiencing toxicity or otherundesirable side effects from a treatment, etc. The present inventionalso provides methods for selecting individuals to whom a therapeuticagent (e.g., a statin) will be administered based on the individual'sgenotype, and methods for selecting individuals for a clinical trial ofa therapeutic agent (e.g., a statin) based on the genotypes of theindividuals (e.g., selecting individuals to participate in the trial whoare most likely to respond positively to the therapeutic agent and/orexcluding individuals from the trial who are unlikely to respondpositively to the therapeutic agent based on their SNP genotype(s), orselecting individuals who are unlikely to respond positively to aparticular therapeutic agent such as a statin based on their SNPgenotype(s) to participate in a clinical trial of another type of drugthat may benefit them). The present invention further provides methodsfor reducing an individual's risk of developing CVD (such as CHD,particularly MI, and hypertension) using a drug treatment (e.g., statintreatment), including preventing recurring CVD (e.g., recurrent CHD,particularly recurrent MI, or recurrent hypertension), when saidindividual carries one or more SNPs identified herein as beingassociated with CVD and/or response to statin treatment.

In Tables 1 and 2, the present invention provides gene information,references to the identification of transcript sequences (SEQ IDNOS:1-307), encoded amino acid sequences (SEQ ID NOS:308-614), genomicsequences (SEQ ID NOS:1015-1400), transcript-based context sequences(SEQ ID NOS:615-1014) and genomic-based context sequences (SEQ IDNOS:1401-4006 and 5414) that contain the SNPs of the present invention,and extensive SNP information that includes observed alleles, allelefrequencies, populations/ethnic groups in which alleles have beenobserved, information about the type of SNP and corresponding functionaleffect, and, for cSNPs, information about the encoded polypeptideproduct. The actual transcript sequences (SEQ ID NOS:1-307), amino acidsequences (SEQ ID NOS:308-614), genomic sequences (SEQ IDNOS:1015-1400), transcript-based SNP context sequences (SEQ IDNOS:615-1014), and genomic-based SNP context sequences (SEQ IDNOS:1401-4006 and 5414), together with primer sequences (SEQ IDNOS:4007-5413 and 5415-5416) are provided in the Sequence Listing.

In certain exemplary embodiments, the invention provides methods foridentifying an individual who has an altered risk for developing CVD,such as CHD (particularly MI) or hypertension (including, for example, afirst incidence and/or a recurrence of the disease), in which the methodcomprises detecting a single nucleotide polymorphism (SNP) in any one ofthe nucleotide sequences of SEQ ID NOS:1-307, SEQ ID NOS:615-1014, SEQID NOS:1015-1400, and SEQ ID NOS:1401-4006 and 5414 in said individual'snucleic acids, wherein the SNP is specified in Table 1 and/or Table 2,and the presence of the SNP is indicative of an altered risk for CVD insaid individual. In certain embodiments, the CVD is CHD (particularlyMI) or hypertension. In certain exemplary embodiments of the invention,SNPs that occur naturally in the human genome are provided as isolatednucleic acid molecules. These SNPs are associated with CVD (particularCHD, especially MI, and hypertension) such that they can have a varietyof uses in the diagnosis, prognosis, treatment, and/or prevention of CVDand related pathologies. In an alternative embodiment, a nucleic acid ofthe invention is an amplified polynucleotide, which is produced byamplification of a SNP-containing nucleic acid template. In anotherembodiment, the invention provides for a variant protein that is encodedby a nucleic acid molecule containing a SNP disclosed herein.

In yet another embodiment of the invention, a reagent for detecting aSNP in the context of its naturally-occurring flanking nucleotidesequences (which can be, e.g., either DNA or mRNA) is provided. Inparticular, such a reagent may be in the form of, for example, ahybridization probe or an amplification primer that is useful in thespecific detection of a SNP of interest. In an alternative embodiment, aprotein detection reagent is used to detect a variant protein that isencoded by a nucleic acid molecule containing a SNP disclosed herein. Apreferred embodiment of a protein detection reagent is an antibody or anantigen-reactive antibody fragment.

Various embodiments of the invention also provide kits comprising SNPdetection reagents, and methods for detecting the SNPs disclosed hereinby employing detection reagents. In a specific embodiment, the presentinvention provides for a method of identifying an individual having anincreased or decreased risk of developing CVD (e.g., CHD, particularlyMI, or hypertension) by detecting the presence or absence of one or moreSNP alleles disclosed herein. In another embodiment, a method fordiagnosis of CVD by detecting the presence or absence of one or more SNPalleles disclosed herein is provided. The present invention alsoprovides methods for evaluating whether an individual is likely (orunlikely) to respond to a treatment (e.g., a therapeutic agent such as astatin) by detecting the presence or absence of one or more SNP allelesdisclosed herein.

The nucleic acid molecules of the invention can be inserted in anexpression vector, such as to produce a variant protein in a host cell.Thus, the present invention also provides for a vector comprising aSNP-containing nucleic acid molecule, genetically-engineered host cellscontaining the vector, and methods for expressing a recombinant variantprotein using such host cells. In another specific embodiment, the hostcells, SNP-containing nucleic acid molecules, and/or variant proteinscan be used as targets in a method for screening and identifyingtherapeutic agents or pharmaceutical compounds useful in the treatmentor prevention of CVD (particularly CHD, such as MI, or hypertension).

An aspect of this invention is a method for treating or preventing CVD,such as CHD (particularly MI) or hypertension (including, for example, afirst occurrence and/or a recurrence of the disease), in a human subjectwherein said human subject harbors a SNP, gene, transcript, and/orencoded protein identified in Tables 1 and 2, which method comprisesadministering to said human subject a therapeutically orprophylactically effective amount of one or more agent(s) counteractingthe effects of the disease, such as by inhibiting (or stimulating) theactivity of a gene, transcript, and/or encoded protein identified inTables 1 and 2. In certain exemplary embodiments, the agent(s) comprisea statin.

Another aspect of this invention is a method for identifying an agentuseful in therapeutically or prophylactically treating CVD (particularlyCHD, such as MI, or hypertension), in a human subject wherein said humansubject harbors a SNP, gene, transcript, and/or encoded proteinidentified in Tables 1 and 2, which method comprises contacting thegene, transcript, or encoded protein with a candidate agent underconditions suitable to allow formation of a binding complex between thegene, transcript, or encoded protein and the candidate agent anddetecting the formation of the binding complex, wherein the presence ofthe complex identifies said agent.

Another aspect of this invention is a method for treating or preventingCVD (such as CHD, particularly MI, or hypertension), in a human subject,in which the method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1 and 2, and

(ii) administering to said subject a therapeutically or prophylacticallyeffective amount of one or more agents (e.g., one or more statins)counteracting the effects of the disease.

Another aspect of the invention is a method for identifying a human whois likely to benefit from a treatment (e.g., a therapeutic agent,particularly a statin), in which the method comprises detecting anallele of one or more SNPs disclosed herein in said human's nucleicacids, wherein the presence of the allele indicates that said human islikely to benefit from the treatment. Another aspect of the invention isa method for identifying a human who is likely to benefit from atreatment (e.g., a therapeutic agent, particularly a statin), in whichthe method comprises detecting an allele of one or more SNPs that are inLD with one or more SNPs disclosed herein in said human's nucleic acids,wherein the presence of the allele of the LD SNP indicates that saidhuman is likely to benefit from the treatment.

Many other uses and advantages of the present invention will be apparentto those skilled in the art upon review of the detailed description ofthe preferred embodiments herein. Solely for clarity of discussion, theinvention is described in the sections below by way of non-limitingexamples.

Description of the Text (ASCII) File Submitted Electronically ViaEFS-WEB

The following text (ASCII) files are submitted electronically viaEFS-Web as part of the instant application:

1) File SEQLIST_CD26ORD.txt provides the Sequence Listing. The SequenceListing provides the transcript sequences (SEQ ID NOS:1-307) and proteinsequences (SEQ ID NOS:308-614) as referred to in Table 1, and genomicsequences (SEQ ID NOS:1015-1400) as referred to in Table 2, for eachCVD-associated gene (or genomic region for intergenic SNPs) thatcontains one or more SNPs of the present invention. Also provided in theSequence Listing are context sequences flanking each SNP, including bothtranscript-based context sequences as referred to in Table 1 (SEQ IDNOS:615-1014) and genomic-based context sequences as referred to inTable 2 (SEQ ID NOS:1401-4006 and 5414). In addition, the SequenceListing provides the primer sequences from Table 5 (SEQ ID NOS:4007-5413and 5415-5416). The context sequences generally provide 100 bp upstream(5′) and 100 bp downstream (3′) of each SNP, with the SNP in the middleof the context sequence, for a total of 200 bp of context sequencesurrounding each SNP. File SEQLIST_CD26ORD.txt is 52,636 KB in size, andwas created on Jul. 8, 2009.

2) File TABLE1_CD26ORD.txt provides Table 1, which is 477 KB in size,and was created on Jul. 7, 2009.

3) File TABLE2_CD26ORD.txt provides Table 2, which is 1,961 KB in size,and was created on Jul. 8, 2009.

4) File TABLE3_CD26ORD.txt provides Table 3, which is 1 KB in size, andwas created on Jul. 6, 2009.

5) File TABLE4_CD26ORD.txt provides Table 4, which is 1 KB in size, andwas created on Jul. 6, 2009.

These text files are hereby incorporated by reference pursuant to 37 CFR1.77(b)(4).

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20130030051A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Description of Table 1 and Table 2

Table 1 and Table 2 (both submitted electronically via EFS-Web) disclosethe SNP and associated gene/transcript/protein information of thepresent invention. For each gene, Table 1 provides a header containinggene, transcript and protein information, followed by a transcript andprotein sequence identifier (SEQ ID NO), and then SNP informationregarding each SNP found in that gene/transcript including thetranscript context sequence. For each gene in Table 2, a header isprovided that contains gene and genomic information, followed by agenomic sequence identifier (SEQ ID NO) and then SNP informationregarding each SNP found in that gene, including the genomic contextsequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table1 presents the SNPs relative to their transcript sequences and encodedprotein sequences, whereas Table 2 presents the SNPs relative to theirgenomic sequences. In some instances Table 2 may also include, after thelast gene sequence, genomic sequences of one or more intergenic regions,as well as SNP context sequences and other SNP information for any SNPsthat lie within these intergenic regions. Additionally, in either Table1 or 2 a “Related Interrogated SNP” may be listed following a SNP whichis determined to be in LD with that interrogated SNP according to thegiven Power value. SNPs can be readily cross-referenced between allTables based on their Celera hCV (or, in some instances, hDV)identification numbers and/or public rs identification numbers, and tothe Sequence Listing based on their corresponding SEQ ID NOs.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in        the Table),    -   a gene symbol, along with an Entrez gene identification number        (Entrez Gene database, National Center for Biotechnology        Information (NCBI), National Library of Medicine, National        Institutes of Health)    -   a gene name,    -   an accession number for the transcript (e.g., RefSeq NM number,        or a Celera hCT identification number if no RefSeq NM number is        available) (Table 1 only),    -   an accession number for the protein (e.g., RefSeq NP number, or        a Celera hCP identification number if no RefSeq NP number is        available) (Table 1 only),    -   the chromosome number of the chromosome on which the gene is        located,    -   an OMIM (“Online Mendelian Inheritance in Man” database, Johns        Hopkins University/NCBI) public reference number for the gene,        and OMIM information such as alternative gene/protein name(s)        and/or symbol(s) in the OMIM entry.

Note that, due to the presence of alternative splice forms, multipletranscript/protein entries may be provided for a single gene entry inTable 1; i.e., for a single Gene Number, multiple entries may beprovided in series that differ in their transcript/protein informationand sequences.

Following the gene/transcript/protein information is a transcriptcontext sequence (Table 1), or a genomic context sequence (Table 2), foreach SNP within that gene.

After the last gene sequence, Table 2 may include additional genomicsequences of intergenic regions (in such instances, these sequences areidentified as “Intergenic region:” followed by a numericalidentification number), as well as SNP context sequences and other SNPinformation for any SNPs that lie within each intergenic region (suchSNPs are identified as “INTERGENIC” for SNP type).

Note that the transcript, protein, and transcript-based SNP contextsequences are all provided in the Sequence Listing. The transcript-basedSNP context sequences are provided in both Table 1 and also in theSequence Listing. The genomic and genomic-based SNP context sequencesare provided in the Sequence Listing. The genomic-based SNP contextsequences are provided in both Table 2 and in the Sequence Listing. SEQID NOs are indicated in Table 1 for the transcript-based contextsequences (SEQ ID NOS:615-1014); SEQ ID NOs are indicated in Table 2 forthe genomic-based context sequences (SEQ ID NOS:1401-4006 and 5414).

The SNP information includes:

-   -   Context sequence (taken from the transcript sequence in Table 1,        the genomic sequence in Table 2) with the SNP represented by its        IUB code, including 100 bp upstream (5′) of the SNP position        plus 100 bp downstream (3′) of the SNP position (the        transcript-based SNP context sequences in Table 1 are provided        in the Sequence Listing as SEQ ID NOS:615-1014; the        genomic-based SNP context sequences in Table 2 are provided in        the Sequence Listing as SEQ ID NOS:1401-4006 and 5414).    -   Celera hCV internal identification number for the SNP (in some        instances, an “hDV” number is given instead of an “hCV” number;        “hDV68873046” may be interchangeably referred to herein as        “hCV29714327”).    -   The corresponding public identification number for the SNP, the        rs number.    -   “SNP Chromosome Position” indicates the nucleotide position of        the SNP along the entire sequence of the chromosome as provided        in NCBI Genome Build 36.    -   SNP position (nucleotide position of the SNP within the given        transcript sequence (Table 1) or within the given genomic        sequence (Table 2)).    -   “Related Interrogated SNP” is the interrogated SNP with which        the listed SNP is in LD at the given value of Power.    -   SNP source (may include any combination of one or more of the        following five codes, depending on which internal sequencing        projects and/or public databases the SNP has been observed in:        “Applera”═SNP observed during the re-sequencing of genes and        regulatory regions of 39 individuals, “Celera”=SNP observed        during shotgun sequencing and assembly of the Celera human        genome sequence, “Celera Diagnostics”=SNP observed during        re-sequencing of nucleic acid samples from individuals who have        a disease, “dbSNP”=SNP observed in the dbSNP public database,        “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP        observed in the Human Gene Mutation Database (HGMD) public        database, “HapMap”=SNP observed in the International HapMap        Project public database, “CSNP”=SNP observed in an internal        Applied Biosystems (Foster City, Calif.) database of coding SNPS        (cSNPs).

Note that multiple “Applera” source entries for a single SNP indicatethat the same SNP was covered by multiple overlapping amplificationproducts and the re-sequencing results (e.g., observed allele counts)from each of these amplification products is being provided.

-   -   Population/allele/allele count information in the format of        [population1(first_allele,countlsecond_allele,count)population2(first_allele,countlsecond_allele,count)        total (first_allele,total countlsecond_allele,total count)]. The        information in this field includes populations/ethnic groups in        which particular SNP alleles have been observed        (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and        “afr”=African-American, “jpn”=Japanese, “ind”=Indian,        “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor,        “no_pop”=no population information available), identified SNP        alleles, and observed allele counts (within each population        group and total allele counts), where available [“-” in the        allele field represents a deletion allele of an        insertion/deletion (“indel”) polymorphism (in which case the        corresponding insertion allele, which may be comprised of one or        more nucleotides, is indicated in the allele field on the        opposite side of the “I”); “-” in the count field indicates that        allele count information is not available]. For certain SNPs        from the public dbSNP database, population/ethnic information is        indicated as follows (this population information is publicly        available in dbSNP): “HISP1”=human individual DNA (anonymized        samples) from 23 individuals of self-described HISPANIC        heritage; “PAC1”=human individual DNA (anonymized samples) from        24 individuals of self-described PACIFIC RIM heritage;        “CAUC1”=human individual DNA (anonymized samples) from 31        individuals of self-described CAUCASIAN heritage; “AFR1”=human        individual DNA (anonymized samples) from 24 individuals of        self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human        individual DNA (anonymized samples) from 102 individuals of        self-described heritage; “PA130299515”; “SC_(—)12_A”═SANGER 12        DNAs of Asian origin from Corielle cell repositories, 6 of which        are male and 6 female; “SC_(—)12_C”═SANGER 12 DNAs of Caucasian        origin from Corielle cell repositories from the CEPH/UTAH        library, six male and six female; “SC_(—)12_AA”═SANGER 12 DNAs        of African-American origin from Corielle cell repositories 6 of        which are male and 6 female; “SC_(—)95_C”=SANGER 95 DNAs of        Caucasian origin from Corielle cell repositories from the        CEPH/UTAH library; and “SC_(—)12_CA”=Caucasians-12 DNAs from        Corielle cell repositories that are from the CEPH/UTAH library,        six male and six female.

Note that for SNPs of “Applera” SNP source, genes/regulatory regions of39 individuals (20 Caucasians and 19 African Americans) werere-sequenced and, since each SNP position is represented by twochromosomes in each individual (with the exception of SNPs on X and Ychromosomes in males, for which each SNP position is represented by asingle chromosome), up to 78 chromosomes were genotyped for each SNPposition. Thus, the sum of the African-American (“afr”) allele counts isup to 38, the sum of the Caucasian allele counts (“cau”) is up to 40,and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count informationcorresponding to each indicated SNP source; i.e., if four SNP sourcesare indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” thenpopulation/allele/count information is provided in four groups which areseparated by semicolons and listed in the same order as the listing ofSNP sources, with each population/allele/count information groupcorresponding to the respective SNP source based on order; thus, in thisexample, the first population/allele/count information group wouldcorrespond to the first listed SNP source (Celera) and the thirdpopulation/allele/count information group separated by semicolons wouldcorrespond to the third listed SNP source (HGBASE); ifpopulation/allele/count information is not available for any particularSNP source, then a pair of semicolons is still inserted as aplace-holder in order to maintain correspondence between the list of SNPsources and the corresponding listing of population/allele/countinformation.

-   -   SNP type (e.g., location within gene/transcript and/or predicted        functional effect) [“MIS-SENSE MUTATION”=SNP causes a change in        the encoded amino acid (i.e., a non-synonymous coding SNP);        “SILENT MUTATION”=SNP does not cause a change in the encoded        amino acid (i.e., a synonymous coding SNP); “STOP CODON        MUTATION”=SNP is located in a stop codon; “NONSENSE        MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is        located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a        3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a        putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative        3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice        site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located        in an acceptor splice site (3′ intron boundary); “CODING        REGION”=SNP is located in a protein-coding region of the        transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is        located in an intron; “hmCS”=SNP is located in a human-mouse        conserved segment; “TFBS”=SNP is located in a transcription        factor binding site; “UNKNOWN”=SNP type is not defined;        “INTERGENIC”=SNP is intergenic, i.e., outside of any gene        boundary].    -   Protein coding information (Table 1 only), where relevant, in        the format of [protein SEQ ID NO, amino acid position, (amino        acid-1, codonl) (amino acid-2, codon2)]. The information in this        field includes SEQ ID NO of the encoded protein sequence,        position of the amino acid residue within the protein identified        by the SEQ ID NO that is encoded by the codon containing the        SNP, amino acids (represented by one-letter amino acid codes)        that are encoded by the alternative SNP alleles (in the case of        stop codons, “X” is used for the one-letter amino acid code),        and alternative codons containing the alternative SNP        nucleotides which encode the amino acid residues (thus, for        example, for missense mutation-type SNPs, at least two different        amino acids and at least two different codons are generally        indicated; for silent mutation-type SNPs, one amino acid and at        least two different codons are generally indicated, etc.). In        instances where the SNP is located outside of a protein-coding        region (e.g., in a UTR region), “None” is indicated following        the protein SEQ ID NO.

Note that SNPs can be cross-referenced between any of Tables 1-22 hereinbased on their hCV and/or rs identification numbers. However, two of theSNPs that are included in the tables may possess two different hCVidentification numbers, as follows:

-   -   SNP hCV25473098 is the same as SNP hCV16173091 set forth in        Tables 1-2.    -   SNP hCV16192174 is the same as SNP hCV22271999 set forth in        Tables 1-2.    -   SNP hCV25640504 can be represented by either genomic context        sequences SEQ ID NOS:2554 or 5414 (each of which is set forth in        Table 2 and the Sequence Listing), and can be assayed using        either allele-specific primers SEQ ID NOS:4580-4581 or SEQ ID        NOS:5415-5416 (any of which can be used in combination with        common primer SEQ ID NO:4582) (each of which allele-specific and        common primers is set forth in Table 5 and the Sequence        Listing).

Description of Table 3 and Table 4

Tables 3 and 4 (both submitted electronically via EFS-Web) provide alist of a subset of SNPs from Table 1 (in the case of Table 3) or Table2 (in the case of Table 4) for which the SNP source falls into one ofthe following three categories: 1) SNPs for which the SNP source is only“Applera” and none other, 2) SNPs for which the SNP source is only“Celera Diagnostics” and none other, and 3) SNPs for which the SNPsource is both “Applera” and “Celera Diagnostics” but none other.

These SNPs have not been observed in any of the public databases (dbSNP,HGBASE, and HGMD), and were also not observed during shotgun sequencingand assembly of the Celera human genome sequence (i.e., “Celera” SNPsource). Tables 3 and 4 provide the hCV identification number (or hDVidentification number for SNPs having “Celera Diagnostics” SNP source)and the SEQ ID NO of the context sequence for each of these SNPs.

Description of Table 5

Table 5 provides sequences (SEQ ID NOS:4007-5413 and 5415-5416) ofprimers that may be used to assay the SNPs disclosed herein byallele-specific PCR or other methods, such as for uses related to CVD.

Table 5 provides the following:

-   -   the column labeled “Marker” provides an hCV identification        number for each SNP that can be detected using the corresponding        primers.    -   the column labeled “Alleles” designates the two alternative        alleles (i.e., nucleotides) at the SNP site. These alleles are        targeted by the allele-specific primers (the allele-specific        primers are shown as Primer 1 and Primer 2). Note that alleles        may be presented in Table 5 based on a different orientation        (i.e., the reverse complement) relative to how the same alleles        are presented in Tables 1-2.    -   the column labeled “Primer 1 (Allele-Specific Primer)” provides        an allele-specific primer that is specific for an allele        designated in the “Alleles” column.    -   the column labeled “Primer 2 (Allele-Specific Primer)” provides        an allele-specific primer that is specific for the other allele        designated in the “Alleles” column.    -   the column labeled “Common Primer” provides a common primer that        is used in conjunction with each of the allele-specific primers        (i.e., Primer 1 and Primer 2) and which hybridizes at a site        away from the SNP position.

All primer sequences are given in the 5′ to 3′ direction.

Each of the nucleotides designated in the “Alleles” column matches or isthe reverse complement of (depending on the orientation of the primerrelative to the designated allele) the 3′ nucleotide of theallele-specific primer (i.e., either Primer 1 or Primer 2) that isspecific for that allele.

Description of Table 6

Table 6 provides a list of LD SNPs that are related to and derived fromcertain interrogated SNPs. The interrogated SNPs, which are shown incolumn 1 (which indicates the hCV identification numbers of eachinterrogated SNP) and column 2 (which indicates the public rsidentification numbers of each interrogated SNP) of Table 6, arestatistically significantly associated with CVD, as described and shownherein, particularly in Tables 7-22 and in the Examples section below.The LD SNPs are provided as an example of SNPs which can also serve asmarkers for disease association based on their being in LD with aninterrogated SNP. The criteria and process of selecting such LD SNPs,including the calculation of the r² value and the r² threshold value,are described in Example 6, below.

In Table 6, the column labeled “Interrogated SNP” presents each markeras identified by its unique hCV identification number. The columnlabeled “Interrogated rs” presents the publicly known rs identificationnumber for the corresponding hCV number. The column labeled “LD SNP”presents the hCV numbers of the LD SNPs that are derived from theircorresponding interrogated SNPs. The column labeled “LD SNP rs” presentsthe publicly known rs identification number for the corresponding hCVnumber. The column labeled “Power” presents the level of power where ther² threshold is set. For example, when power is set at 0.51, thethreshold r² value calculated therefrom is the minimum r² that an LD SNPmust have in reference to an interrogated SNP, in order for the LD SNPto be classified as a marker capable of being associated with a diseasephenotype at greater than 51% probability. The column labeled “Thresholdr²” presents the minimum value of r² that an LD SNP must meet inreference to an interrogated SNP in order to qualify as an LD SNP. Thecolumn labeled “r²” presents the actual r² value of the LD SNP inreference to the interrogated SNP to which it is related.

Description of Tables 7-22

Tables 7-22 provide the results of statistical analyses for SNPsdisclosed in Tables 1 and 2 (SNPs can be cross-referenced between allthe tables herein based on their hCV and/or rs identification numbers).The results shown in Tables 7-22 provide support for the association ofthese SNPs with CVD, particularly CHD (especially MI) and/orhypertension.

Table 7 provides association test results from two MI case-controlstudies (see Example 1 below).

Table 8 provides descriptive information by race and GOSR2 genotype (seeExample 1 below).

Table 9 provides OR and 95% CI for the association between GOSR2(Lys67Arg, rs197922), hypertension, and carotid artery thickness (seeExample 1 below).

Table 10 provides SNPs surrounding GOSR2SNP rs197922 (hCV2275273) thatare associated with CVD, particularly CHD, and especially MI (seeExample 3 below).

Table 11 provides risk factors for MI in participants of threecase-control studies (see Example 2 below).

Table 12 provides twenty-four SNPs associated with MI in Study 1 (UCSF)and Study 2 (UCSF) (see Example 2 below).

Table 13 provides results for genotypic association of five SNPs inStudy 3 (CCF) (see Example 2 below).

Table 14 provides SNPs surrounding the ENO1 SNP rs1325920 (hCV8824241)that are associated with CVD, particularly CHD, and especially MI (seeExample 3 below).

Table 15 provides SNPs surrounding the FXN SNP rs10890 (hCV1463226) thatare associated with CVD, particularly CHD, and especially MI (seeExample 3 below).

Table 16 provides SNPs surrounding the RERE SNP rs10779705 (hCV32055477)that are associated with CVD, particularly CHD, and especially MI (seeExample 3 below).

Table 17 provides SNPs surrounding VAMP8 rs1010 (hCV2091644) that areassociated with CVD, particularly CHD, and especially MI (see Example 3below).

Tables 18 and 19 provide SNPs surrounding the LPA SNP rs3798220(hCV25930271) that are associated with CVD, particularly CHD, andespecially MI. Table 18 provides results of an analysis of the UCSF1sample set, and Table 19 provides results of a meta-analysis of theUCSF1 and UCSF2 sample sets combined. The SNPs provided in Table 19 arealso associated with Lp(a) levels (see Example 3 below).

Table 20 provides SNPs (from a functional genome scan (FGS)) associatedwith CVD, particularly CHD, and especially MI, in two studies (seeExample 4 below).

Table 21 provides SNPs associated with reduction of CHD risk,particularly risk for MI and recurrent MI, by Pravastatin in the CAREstudy, and Table 22 provides SNPs associated with risk of CHD,particularly risk for MI and recurrent MI, in the placebo arm of theCARE study. The SNPs provided in Table 22 are a subset of the SNPsprovided in Table 21; thus, the SNPs provided in Table 22 are associatedwith both increased CHD risk as well as reduction of CHD risk by statintreatment (e.g., Pravastatin) (see Example 5 below).

Table 21 provides SNPs for which the effect of pravastatin on theprimary endpoint of the CARE study (identified as “endpt1” in theEndpoint column) or the recurrent MI endpoint (identified as “rmi” inthe Endpoint column) was analyzed by genotype subgroups and for whichpravastatin reduced risk in one genotype subgroup but not in another(P-interaction between statin treatment and genotype for the enpdpoint<0.1).

Table 22 provides a subset of SNPs from Table 21 that were associated(p<0.1) with time to occurrence of first event, either the CARE primaryendpoint (“endpt1”) or recurrent MI endpoint (“rmi”), in the placebogroup of the CARE study. In Table 22, the HR (including lower and upperconfidence intervals) and p-values indicated for each SNP correspond toAllele 1 (Allele 2 is the reference allele, which is considered to haveHR=1).

In Tables 21-22, the column labeled “Endpoint” indicates whether theendpoint that was analyzed was the primary endpoint of the CARE study (acomposite endpoint of fatal coronary event or nonfatal MI, andidentified as “endpt1”) or a composite endpoint of confirmed fatal ornonfatal MI (identified as “rmi”). Also in Tables 21-22, the columnlabeled “Events” indicates the number of individuals in the CARE studywho had an event (a fatal coronary event or nonfatal MI if “endpt1” isindicated in the Endpoint column, or a fatal or nonfatal MI if “rmi” isindicated in the Endpoint column). Table 22 indicates, for each SNP, thenumber of individuals in the placebo arm of the CARE study who had anevent (column labeled “Events (placebo arm)”) and the total number ofindividuals (column labeled “Total Patients (placebo arm)”). Table 21indicates, for each SNP, the number of individuals who had an event ineach of the Pravastatin and placebo arms of the CARE study (columnslabeled “Events (Pravastatin arm)” and “Events (placebo arm)”,respectively) and the number of individuals who did not have an event ineach of the Pravastatin and placebo arms of the CARE study (columnslabeled “Nonevent (Pravastatin arm)” and “Nonevent (placebo arm)”,respectively).

Throughout Tables 7-22, with respect to model, “add” is additive, “rec”is recessive, “dom” is dominant, “het” is heterozygotes compared withreference homozygotes, and “hom” is non-reference homozygotes comparedwith reference homozygotes, and with respect to strata, “M” is malesonly and “F” is females only.

Throughout Tables 7-22, “OR” refers to the odds ratio, “HR” refers tothe hazard ratio, and “90% CI” or “95% CI” refers to the 90% or 95%confidence interval (respectively) for the odds ratio or hazard ratio(“OR95U” and “OR95L” refer to the upper and lower 95% confidenceintervals, respectively, for the odds ratio; and “HR95U” and “HR95L”refer to the upper and lower 95% confidence intervals, respectively, forthe hazard ratio). Odds ratios (OR) or hazard ratios (HR) that aregreater than one indicate that a given allele is a risk allele (whichmay also be referred to as a susceptibility allele), whereas odds ratiosthat are less than one indicate that a given allele is a non-risk allele(which may also be referred to as a protective allele). For a given riskallele, the other alternative allele at the SNP position (which can bederived from the information provided in Tables 1-2, for example) may beconsidered a non-risk allele. For a given non-risk allele, the otheralternative allele at the SNP position may be considered a risk allele.

Thus, with respect to disease risk (e.g., CVD such as CHD, particularlyMI, or hypertension), if the risk estimate (odds ratio or hazard ratio)for a particular allele at a SNP position is greater than one, thisindicates that an individual with this particular allele has a higherrisk for the disease than an individual who has the other allele at theSNP position. In contrast, if the risk estimate (odds ratio or hazardratio) for a particular allele is less than one, this indicates that anindividual with this particular allele has a reduced risk for thedisease compared with an individual who has the other allele at the SNPposition.

With respect to drug response (e.g., response to a statin), if the riskestimate (odds ratio or hazard ratio) of those treated with the drug(e.g., a statin) compared with those treated with a placebo within aparticular genotype is less than one, this indicates that an individualwith this particular genotype would benefit from the drug (an odds ratioor hazard ratio equal to one would indicate that the drug has noeffect). As used herein, the term “benefit” (with respect to apreventive or therapeutic drug treatment) is defined as achieving areduced risk for a disease that the drug is intended to treat or prevent(e.g., CVD such as CHD, particularly MI, or hypertension) byadministering the drug treatment, compared with the risk for the diseasein the absence of receiving the drug treatment (or receiving a placeboin lieu of the drug treatment) for the same genotype.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides SNPs associated with cardiovasculardiseases (CVD), particularly coronary heart disease (CHD), especiallymyocardial infarction (MI), and hypertension.

The present invention further provides nucleic acid molecules containingthese SNPs, methods and reagents for the detection of the SNPs disclosedherein, uses of these SNPs for the development of detection reagents,and assays or kits that utilize such reagents. The SNPs disclosed hereinare useful for diagnosing, prognosing, screening for, and evaluatingpredisposition to CVD and related pathologies in humans. The SNPsdisclosed herein may also be used for predicting, screening for, andevaluating response to a treatment (e.g., a therapeutic agent,particularly a statin), particularly treatment or prevention of CVD, inhumans. Furthermore, such SNPs and their encoded products are usefultargets for the development of therapeutic and preventive agents.

A large number of SNPs have been identified from re-sequencing DNA from39 individuals, and they are indicated as “Applera” SNP source in Tables1-2. Their allele frequencies observed in each of the Caucasian andAfrican-American ethnic groups are provided. Additional SNPs includedherein were previously identified during “shotgun” sequencing andassembly of the human genome, and they are indicated as “Celera” SNPsource in Tables 1 and 2. Furthermore, the information provided inTables 1 and 2, particularly the allele frequency information obtainedfrom 39 eindividuals and the identification of the precise position ofeach SNP within each gene/transcript, allows haplotypes (i.e., groups ofSNPs that are co-inherited) to be readily inferred. The presentinvention encompasses SNP haplotypes, as well as individual SNPs.

Thus, the present invention provides individual SNPs associated with CVD(particularly CHD, especially MI, and hypertension), as well ascombinations of SNPs and haplotypes, polymorphic/variant transcriptsequences (SEQ ID NOS:1-307) and genomic sequences (SEQ IDNOS:1015-1400) containing SNPs, encoded amino acid sequences (SEQ IDNOS:308-614), and both transcript-based SNP context sequences (SEQ IDNOS:615-1014) and genomic-based SNP context sequences (SEQ IDNOS:1401-4006 and 5414) (transcript sequences, protein sequences, andtranscript-based SNP context sequences are provided in Table 1 and theSequence Listing; genomic sequences and genomic-based SNP contextsequences are provided in Table 2 and the Sequence Listing), methods ofdetecting these polymorphisms in a test sample, methods of determiningthe risk of an individual of having or developing CVD, methods ofdetermining if an individual is likely to respond to a particulartreatment such as a therapeutic agent such as a statin (particularly fortreating or preventing CVD), methods of screening for compounds usefulfor treating disorders associated with a variant gene/protein such asCVD, compounds identified by these screening methods, methods of usingthe disclosed SNPs to select a treatment/preventive strategy ortherapeutic agent, methods of treating or preventing a disorderassociated with a variant gene/protein, and methods of using the SNPs ofthe present invention for human identification.

The present invention further provides methods for selecting orformulating a treatment regimen (e.g., methods for determining whetheror not to administer a therapeutic agent, particularly a statin, to anindividual having CVD, or who is at risk for developing CVD in thefuture, or who has previously had CVD, methods for selecting aparticular treatment regimen such as dosage and frequency ofadministration of a therapeutic agent (e.g., a statin), or a particularform/type of a therapeutic agent such as a particular pharmaceuticalformulation or compound, methods for administering an alternativetreatment to individuals who are predicted to be unlikely to respondpositively to a particular treatment, etc.), and methods for determiningthe likelihood of experiencing toxicity or other undesirable sideeffects from a treatment, etc. The present invention also providesmethods for selecting individuals to whom a therapeutic agent (e.g., astatin) will be administered based on the individual's genotype, andmethods for selecting individuals for a clinical trial of a therapeuticagent (e.g., a statin) based on the genotypes of the individuals (e.g.,selecting individuals to participate in the trial who are most likely torespond positively to a therapeutic agent and/or excluding individualsfrom the trial who are unlikely to respond positively to a therapeuticagent based on their SNP genotype(s), or selecting individuals who areunlikely to respond positively to a particular agent such as a statinbased on their SNP genotype(s) to participate in a clinical trial ofanother thereapeutic agent that may benefit them).

The present invention may include novel SNPs associated with CVD and/orstatin response, as well as SNPs that were previously known in the art,but were not previously known to be associated with CVD and/or statinresponse. Accordingly, the present invention may provide novelcompositions and methods based on novel SNPs disclosed herein, and mayalso provide novel methods of using known, but previously unassociated,SNPs in methods relating to, for example, evaluating an individual'slikelihood of having or developing CVD (particularly CHD, such as MI,and hypertension), predicting the likelihood of an individualexperiencing a reccurrence of CVD (e.g., experiencing recurrent CHD,particularly recurrent MI, or recurrent hypertension), prognosing theseverity of CVD in an individual, or prognosing an individual's recoveryfrom CVD, and methods relating to evaluating an individual's likelihoodof responding to a treatment such as a particular therapeutic agent,especially a statin (particularly for treatment, including preventivetreatment, of CVD). In Tables 1 and 2, known SNPs are identified basedon the public database in which they have been observed, which isindicated as one or more of the following SNP types: “dbSNP”=SNPobserved in dbSNP, “HGBASE”=SNP observed in HGBASE, and “HGMD”=SNPobserved in the Human Gene Mutation Database (HGMD).

Particular SNP alleles of the present invention can be associated witheither an increased risk of having or developing CVD (e.g., CHD, such asMI, or hypertension) or increased likelihood of responding to atreatment such as a statin (particularly treatment, including preventivetreatment, of CVD), or a decreased risk of having or developing CVD ordecreased likelihood of responding to a treatment. Thus, whereas certainSNPs (or their encoded products) can be assayed to determine whether anindividual possesses a SNP allele that is indicative of an increasedrisk of having or developing CVD (e.g., CHD, such as MI, orhypertension) or increased likelihood of responding to a treatment,other SNPs (or their encoded products) can be assayed to determinewhether an individual possesses a SNP allele that is indicative of adecreased risk of having or developing CVD or decreased likelihood ofresponding to a treatment. Similarly, particular SNP alleles of thepresent invention can be associated with either an increased ordecreased likelihood of having a reccurrence of CVD (e.g., recurrentCHD, particularly recurrent MI, or recurrent hypertension), of fullyrecovering from CVD, of experiencing toxic effects from a particulartreatment or therapeutic compound, etc. The term “altered” may be usedherein to encompass either of these two possibilities (e.g., anincreased or a decreased risk/likelihood). SNP alleles that areassociated with a decreased risk of having or developing CVD (e.g., CHD,such as MI, or hypertension) may be referred to as “protective” alleles,and SNP alleles that are associated with an increased risk of having ordeveloping CVD may be referred to as “susceptibility” alleles, “risk”alleles, or “risk factors”.

Those skilled in the art will readily recognize that nucleic acidmolecules may be double-stranded molecules and that reference to aparticular site on one strand refers, as well, to the corresponding siteon a complementary strand. In defining a SNP position, SNP allele, ornucleotide sequence, reference to an adenine, a thymine (uridine), acytosine, or a guanine at a particular site on one strand of a nucleicacid molecule also defines the thymine (uridine), adenine, guanine, orcytosine (respectively) at the corresponding site on a complementarystrand of the nucleic acid molecule. Thus, reference may be made toeither strand in order to refer to a particular SNP position, SNPallele, or nucleotide sequence. Probes and primers, may be designed tohybridize to either strand and SNP genotyping methods disclosed hereinmay generally target either strand. Throughout the specification, inidentifying a SNP position, reference is generally made to theprotein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the presentinvention include peptides, polypeptides, proteins, or fragmentsthereof, that contain at least one amino acid residue that differs fromthe corresponding amino acid sequence of the art-knownpeptide/polypeptide/protein (the art-known protein may beinterchangeably referred to as the “wild-type,” “reference,” or “normal”protein). Such variant peptides/polypeptides/proteins can result from acodon change caused by a nonsynonymous nucleotide substitution at aprotein-coding SNP position (i.e., a missense mutation) disclosed by thepresent invention. Variant peptides/polypeptides/proteins of the presentinvention can also result from a nonsense mutation (i.e., a SNP thatcreates a premature stop codon, a SNP that generates a read-throughmutation by abolishing a stop codon), or due to any SNP disclosed by thepresent invention that otherwise alters the structure, function,activity, or expression of a protein, such as a SNP in a regulatoryregion (e.g. a promoter or enhancer) or a SNP that leads to alternativeor defective splicing, such as a SNP in an intron or a SNP at anexon/intron boundary. As used herein, the terms “polypeptide,”“peptide,” and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position(wherein at least two alternative nucleotides are present in thepopulation at the SNP position, in accordance with the inherentdefinition of a SNP) or may refer to an amino acid residue that isencoded by the codon which contains the SNP position (where thealternative nucleotides that are present in the population at the SNPposition form alternative codons that encode different amino acidresidues). An “allele” may also be referred to herein as a “variant”.Also, an amino acid residue that is encoded by a codon containing aparticular SNP may simply be referred to as being encoded by the SNP.

A phrase such as “as represented by”, “as shown by”, “as symbolized by”,or “as designated by” may be used herein to refer to a SNP within asequence (e.g., a polynucleotide context sequence surrounding a SNP),such as in the context of “a polymorphism as represented by position 101of SEQ ID NO:X or its complement”. Typically, the sequence surrounding aSNP may be recited when referring to a SNP, however the sequence is notintended as a structural limitation beyond the specific SNP positionitself. Rather, the context sequence is recited merely as a way ofreferring to the SNP (in this example, “SEQ ID NO:X or its complement”is recited in order to refer to the SNP located at position 101 of SEQID NO:X, but SEQ ID NO:X or its complement is not intended as astructural limitation beyond the specific SNP position itself). In otherwords, it is recognized that the context sequence of SEQ ID NO:X in thisexample may contain one or more polymorphic nucleotide positions outsideof position 101 and therefore an exact match over the full-length of SEQID NO:X is irrelevant since SEQ ID NO:X is only meant to provide contextfor referring to the SNP at position 101 of SEQ ID NO:X Likewise, thelength of the context sequence is also irrelevant (100 nucleotides oneach side of a SNP position has been arbitrarily used in the presentapplication as the length for context sequences merely for convenienceand because 201 nucleotides of total length is expected to providesufficient uniqueness to unambiguously identify a given nucleotidesequence). Thus, since a SNP is a variation at a single nucleotideposition, it is customary to refer to context sequence (e.g., SEQ IDNO:X in this example) surrounding a particular SNP position in order touniquely identify and refer to the SNP. Alternatively, a SNP can bereferred to by a unique identification number such as a public “rs”identification number or an internal “hCV” identification number, suchas provided herein for each SNP (e.g., in Tables 1-2).

As used herein, the term “benefit” (with respect to a preventive ortherapeutic drug treatment such as a statin) is defined as achieving areduced risk for a disease that the drug (e.g., statin) is intended totreat or prevent (e.g., CVD such as CHD, particularly MI, andhypertension) by administrating the drug treatment, compared with therisk for the disease in the absence of receiving the drug treatment (orreceiving a placebo in lieu of the drug treatment) for the samegenotype. The term “benefit” may be used herein interchangeably withterms such as “respond positively” or “positively respond”.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably, and may include, but are not limited to, small moleculecompounds, biologics (e.g., antibodies, proteins, protein fragments,fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g.,antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc.,which may be used for therapeutic and/or preventive treatment of adisease (e.g., CVD such as CHD, particularly MI, or hypertension).

As used herein, a “drug”, “therapeutic agent”, or “treatment”, mayinclude any agent used in the treatment (including therapeutic orpreventive treatment) of CVD, particularly CHD (e.g., MI) orhypertension, such as, for example, a statin such as pravastatin(Pravachol®), atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin(Mevacor®), rosuvastatin (Crestor®), simvastatin (Zocor®), andstorvastatin, as well as combination therapies that include a statinsuch as simvastatin+ezetimibe (Vytorin®), lovastatin+niacinextended-release (Advicor®), and atorvastatin+amlodipine besylate(Caduet®).

Hormone Replacement Therapy (HRT)

Certain aspects of the invention relate to methods of using SNPrs3798220 (which is also referred to herein as hCV25930271) forutilities related to hormone replacement therapy (HRT), particularlymethods that relate to carriers of the rs3798220 risk allele (C)benefiting from hormone replacement therapy.

SNP rs3798220, which is in the LPA gene, is associated with risk of CVD,particularly MI (as described herein, particularly in Example 2 below;also see Luke et al. ATVB 2007; 27:2030-2036, which is incorporatedherein by reference in its entirety). SNP rs3798220 is also associatedwith Lp(a) levels. Shilpak et al. (JAMA. 2000; 283:1845) have shown inthe HERS study that women in the hormone replacement therapy(estrogen+progestin treatment) group with high baseline Lp(a) havesignificant reduction of cardiovascular events compared with placebo.About 70% of carriers of the rs3798220 risk allele (C) have very highLp(a) levels.

Accordingly, certain exemplary embodiments of the invention providemethods of using SNP rs3798220 (hCV25930271) for utilities related toHRT, such as methods of determining whether an individual will benefitfrom HRT based on which allele the individual possesses at SNP rs3798220(e.g., if an individual possesses the rs3798220 risk allele (C), thenthat individual would be identified as an individual who would benefitfrom HRT), methods of determining an individual's risk for CVD(particularly cardiovascular events such as MI) following HRT based onwhich allele the individual possesses at SNP rs3798220 (e.g., if anindividual possesses the rs3798220 risk allele (C), then that individualwould be identified as an individual who would have a reduced risk forcardiovascular events such as MI following HRT as compared to theindividual's risk for cardiovascular events in the absence of HRT (e.g.,as compared with placebo)), and methods of treating an individual withHRT based on having identified that individual as someone who would bepredicted to benefit from HRT (e.g., have a reduced risk for CVD,particularly cardiovascular events such as MI, following HRT) based onwhich allele they possess at SNP rs3798220 (e.g., if an individualpossesses the rs3798220 risk allele (C), then that individual would betreated with HRT, since it would therefore be predicted that theindividual would benefit from HRT), as well as other related methods.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's risk for CVD such as CHD,particularly MI, or hypertension), or an individual's predicted drugresponsiveness (e.g., response to statin treatment), based on assayingone or more SNPs disclosed herein, and/or an individual'sallele(s)/genotype at one or more SNPs disclosed herein, etc.), and/orany other information pertaining to a test, may be referred to herein asa “report”. A tangible report can optionally be generated as part of atesting process (which may be interchangeably referred to herein as“reporting”, or as “providing” a report, “producing” a report, or“generating” a report).

Examples of tangible reports may include, but are not limited to,reports in paper (such as computer-generated printouts of test results)or equivalent formats and reports stored on computer readable medium(such as a CD, USB flash drive or other removable storage device,computer hard drive, or computer network server, etc.). Reports,particularly those stored on computer readable medium, can be part of adatabase, which may optionally be accessible via the internet (such as adatabase of patient records or genetic information stored on a computernetwork server, which may be a “secure database” that has securityfeatures that limit access to the report, such as to allow only thepatient and the patient's medical practioners to view the report whilepreventing other unauthorized individuals from viewing the report, forexample). In addition to, or as an alternative to, generating a tangiblereport, reports can also be displayed on a computer screen (or thedisplay of another electronic device or instrument).

A report can include, for example, an individual's risk for CVD, such asCHD (e.g., MI) or hypertension, or may just include theallele(s)/genotype that an individual carries at one or more SNPsdisclosed herein, which may optionally be linked to informationregarding the significance of having the allele(s)/genotype at the SNP(for example, a report on computer readable medium such as a networkserver may include hyperlink(s) to one or more journal publications orwebsites that describe the medical/biological implications, such asincreased or decreased disease risk, for individuals having a certainallele/genotype at the SNP). Thus, for example, the report can includedisease risk or other medical/biological significance (e.g., drugresponsiveness, etc.) as well as optionally also including theallele/genotype information, or the report may just includeallele/genotype information without including disease risk or othermedical/biological significance (such that an individual viewing thereport can use the allele/genotype information to determine theassociated disease risk or other medical/biological significance from asource outside of the report itself, such as from a medical practioner,publication, website, etc., which may optionally be linked to the reportsuch as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms maybe used herein interchangeably), such as to the individual who wastested, a medical practitioner (e.g., a doctor, nurse, clinicallaboratory practitioner, genetic counselor, etc.), a healthcareorganization, a clinical laboratory, and/or any other party or requesterintended to view or possess the report. The act of “transmitting” or“communicating” a report can be by any means known in the art, based onthe format of the report. Furthermore, “transmitting” or “communicating”a report can include delivering a report (“pushing”) and/or retrieving(“pulling”) a report. For example, reports can betransmitted/communicated by various means, including being physicallytransferred between parties (such as for reports in paper format) suchas by being physically delivered from one party to another, or by beingtransmitted electronically or in signal form (e.g., via e-mail or overthe internet, by facsimile, and/or by any wired or wirelesscommunication methods known in the art) such as by being retrieved froma database stored on a computer network server, etc.

In certain exemplary embodiments, the invention provides computers (orother apparatus/devices such as biomedical devices or laboratoryinstrumentation) programmed to carry out the methods described herein.For example, in certain embodiments, the invention provides a computerprogrammed to receive (i.e., as input) the identity (e.g., the allele(s)or genotype at a SNP) of one or more SNPs disclosed herein and provide(i.e., as output) the disease risk (e.g., an individual's risk for CVDsuch as CHD, particularly MI, or hypertension) or other result (e.g.,disease diagnosis or prognosis, drug responsiveness, etc.) based on theidentity of the SNP(s). Such output (e.g., communication of diseaserisk, disease diagnosis or prognosis, drug responsiveness, etc.) may be,for example, in the form of a report on computer readable medium,printed in paper form, and/or displayed on a computer screen or otherdisplay.

In various exemplary embodiments, the invention further provides methodsof doing business (with respect to methods of doing business, the terms“individual” and “customer” are used herein interchangeably). Forexample, exemplary methods of doing business can comprise assaying oneor more SNPs disclosed herein and providing a report that includes, forexample, a customer's risk for CVD such as CHD, particularly MI, orhypertension (based on which allele(s)/genotype is present at theassayed SNP(s)) and/or that includes the allele(s)/genotype at theassayed SNP(s) which may optionally be linked to information (e.g.,journal publications, websites, etc.) pertaining to disease risk orother biological/medical significance such as by means of a hyperlink(the report may be provided, for example, on a computer network serveror other computer readable medium that is internet-accessible, and thereport may be included in a secure database that allows the customer toaccess their report while preventing other unauthorized individuals fromviewing the report), and optionally transmitting the report. Customers(or another party who is associated with the customer, such as thecustomer's doctor, for example) can request/order (e.g., purchase) thetest online via the internet (or by phone, mail order, at anoutlet/store, etc.), for example, and a kit can be sent/delivered (orotherwise provided) to the customer (or another party on behalf of thecustomer, such as the customer's doctor, for example) for collection ofa biological sample from the customer (e.g., a buccal swab forcollecting buccal cells), and the customer (or a party who collects thecustomer's biological sample) can submit their biological samples forassaying (e.g., to a laboratory or party associated with the laboratorysuch as a party that accepts the customer samples on behalf of thelaboratory, a party for whom the laboratory is under the control of(e.g., the laboratory carries out the assays by request of the party orunder a contract with the party, for example), and/or a party thatreceives at least a portion of the customer's payment for the test). Thereport (e.g., results of the assay including, for example, thecustomer's disease risk and/or allele(s)/genotype at the assayed SNP(s))may be provided to the customer by, for example, the laboratory thatassays the SNP(s) or a party associated with the laboratory (e.g., aparty that receives at least a portion of the customer's payment for theassay, or a party that requests the laboratory to carry out the assaysor that contracts with the laboratory for the assays to be carried out)or a doctor or other medical practitioner who is associated with (e.g.,employed by or having a consulting or contracting arrangement with) thelaboratory or with a party associated with the laboratory, or the reportmay be provided to a third party (e.g., a doctor, genetic counselor,hospital, etc.) which optionally provides the report to the customer. Infurther embodiments, the customer may be a doctor or other medicalpractitioner, or a hospital, laboratory, medical insurance organization,or other medical organization that requests/orders (e.g., purchases)tests for the purposes of having other individuals (e.g., their patientsor customers) assayed for one or more SNPs disclosed herein andoptionally obtaining a report of the assay results.

In certain exemplary methods of doing business, a kit for collecting abiological sample (e.g., a buccal swab for collecting buccal cells, orother sample collection device) is provided to a medical practitioner(e.g., a physician) which the medical practitioner uses to obtain asample (e.g., buccal cells, saliva, blood, etc.) from a patient, thesample is then sent to a laboratory (e.g., a CLIA-certified laboratory)or other facility that tests the sample for one or more SNPs disclosedherein (e.g., to determine the genotype of one or more SNPs disclosedherein, such as to determine the patient's risk for CVD such as CHD,particularly MI, or hypertension), and the results of the test (e.g.,the patient's genotype at one or more SNPs disclosed herein and/or thepatient's disease risk based on their SNP genotype) are provided back tothe medical practitioner (and/or directly to the patient and/or toanother party such as a hospital, medical insurance company, geneticcounselor, etc.) who may then provide or otherwise convey the results tothe patient. The results are typically provided in the form of a report,such as described above.

In certain further exemplary methods of doing business, kits forcollecting a biological sample from a customer (e.g., a buccal swab forcollecting buccal cells, or other sample collection device) are provided(e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy,general merchandise store, or any other desirable outlet), online viathe internet, by mail order, etc., whereby customers can obtain (e.g.,purchase) the kits, collect their own biological samples, and submit(e.g., send/deliver via mail) their samples to a laboratory (e.g., aCLIA-certified laboratory) or other facility which tests the samples forone or more SNPs disclosed herein (e.g., to determine the genotype ofone or more SNPs disclosed herein, such as to determine the customer'srisk for CVD such as CHD, particularly MI, or hypertension) and providesthe results of the test (e.g., of the customer's genotype at one or moreSNPs disclosed herein and/or the customer's disease risk based on theirSNP genotype) back to the customer and/or to a third party (e.g., aphysician or other medical practitioner, hospital, medical insurancecompany, genetic counselor, etc.). The results are typically provided inthe form of a report, such as described above. If the results of thetest are provided to a third party, then this third party may optionallyprovide another report to the customer based on the results of the test(e.g., the result of the test from the laboratory may provide thecustomer's genotype at one or more SNPs disclosed herein without diseaserisk information, and the third party may provide a report of thecustomer's disease risk based on this genotype result).

Certain further embodiments of the invention provide a system fordetermining an individual's CVD risk (e.g., risk for CHD, particularlyMI, or hypertension), or whether an individual will benefit from statintreatment (or other therapy) in reducing CVD risk. Certain exemplarysystems comprise an integrated “loop” in which an individual (or theirmedical practitioner) requests a determination of such individual's CVDrisk (or drug response, such as response to statin treatment, etc.),this determination is carried out by testing a sample from theindividual, and then the results of this determination are provided backto the requestor. For example, in certain systems, a sample (e.g.,buccal cells, saliva, blood, etc.) is obtained from an individual fortesting (the sample may be obtained by the individual or, for example,by a medical practitioner), the sample is submitted to a laboratory (orother facility) for testing (e.g., determining the genotype of one ormore SNPs disclosed herein), and then the results of the testing aresent to the patient (which optionally can be done by first sending theresults to an intermediary, such as a medical practioner, who thenprovides or otherwise conveys the results to the individual and/or actson the results), thereby forming an integrated loop system fordetermining an individual's CVD risk (or drug response, etc.). Theportions of the system in which the results are transmitted (e.g.,between any of a testing facility, a medical practitioner, and/or theindividual) can be carried out by way of electronic or signaltransmission (e.g., by computer such as via e-mail or the internet, byproviding the results on a website or computer network server which mayoptionally be a secure database, by phone or fax, or by any other wiredor wireless transmission methods known in the art). Optionally, thesystem can further include a risk reduction component (i.e., a diseasemanagement system) as part of the integrated loop (for an example of adisease management system, see U.S. Pat. No. 6,770,029, “Diseasemanagement system and method including correlation assessment”). Forexample, the results of the test can be used to reduce the risk of thedisease in the individual who was tested, such as by implementing apreventive therapy regimen (e.g., administration of a drug regimen suchas a statin treatment for reducing CVD risk), modifying the individual'sdiet, increasing exercise, reducing stress, and/or implementing anyother physiological or behavioral modifications in the individual withthe goal of reducing disease risk. For reducing CVD risk (e.g., risk forCHD, particularly MI, or hypertension), this may include any means usedin the art for improving aspects of an individual's health relevant toreducing CVD risk. Thus, in exemplary embodiments, the system iscontrolled by the individual and/or their medical practioner in that theindividual and/or their medical practioner requests the test, receivesthe test results back, and (optionally) acts on the test results toreduce the individual's disease risk, such as by implementing a diseasemanagement system.

The various methods described herein, such as correlating the presenceor absence of a polymorphism with an altered (e.g., increased ordecreased) risk (or no altered risk) for CVD such as CHD, particularlyMI, or hypertension (and/or correlating the presence or absence of apolymorphism with the predicted response of an individual to a drug suchas a statin), can be carried out by automated methods such as by using acomputer (or other apparatus/devices such as biomedical devices,laboratory instrumentation, or other apparatus/devices having a computerprocessor) programmed to carry out any of the methods described herein.For example, computer software (which may be interchangeably referred toherein as a computer program) can perform the step of correlating thepresence or absence of a polymorphism in an individual with an altered(e.g., increased or decreased) risk (or no altered risk) for CVD(particularly risk for CHD, such as MI, or hypertension) for theindividual. Computer software can also perform the step of correlatingthe presence or absence of a polymorphism in an individual with thepredicted response of the individual to a drug such as a statin.Accordingly, certain embodiments of the invention provide a computer (orother apparatus/device) programmed to carry out any of the methodsdescribed herein.

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of thepresent invention that is associated with CVD (particularly CHD,especially MI, or hypertension), including the transcript sequences (SEQID NOS:1-307), genomic sequences (SEQ ID NOS:1015-1400), and proteinsequences (SEQ ID NOS:308-614) of the encoded gene products (with theSNPs indicated by IUB codes in the nucleic acid sequences). In addition,Tables 1 and 2 include SNP context sequences, which generally include100 nucleotide upstream (5′) plus 100 nucleotides downstream (3′) ofeach SNP position (SEQ ID NOS:615-1014 correspond to transcript-basedSNP context sequences disclosed in Table 1, and SEQ ID NOS:1401-4006 and5414 correspond to genomic-based context sequences disclosed in Table2), the alternative nucleotides (alleles) at each SNP position, andadditional information about the variant where relevant, such as SNPtype (coding, missense, splice site, UTR, etc.), human populations inwhich the SNP was observed, observed allele frequencies, informationabout the encoded protein, etc.

Isolated Nucleic Acid Molecules

The present invention provides isolated nucleic acid molecules thatcontain one or more SNPs disclosed Table 1 and/or Table 2. Isolatednucleic acid molecules containing one or more SNPs disclosed in at leastone of Tables 1 and 2 may be interchangeably referred to throughout thepresent text as “SNP-containing nucleic acid molecules.” Isolatednucleic acid molecules may optionally encode a full-length variantprotein or fragment thereof. The isolated nucleic acid molecules of thepresent invention also include probes and primers (which are describedin greater detail below in the section entitled “SNP DetectionReagents”), which may be used for assaying the disclosed SNPs, andisolated full-length genes, transcripts, cDNA molecules, and fragmentsthereof, which may be used for such purposes as expressing an encodedprotein.

As used herein, an “isolated nucleic acid molecule” generally is onethat contains a SNP of the present invention or one that hybridizes tosuch molecule such as a nucleic acid with a complementary sequence, andis separated from most other nucleic acids present in the natural sourceof the nucleic acid molecule. Moreover, an “isolated” nucleic acidmolecule, such as a cDNA molecule containing a SNP of the presentinvention, can be substantially free of other cellular material, orculture medium when produced by recombinant techniques, or chemicalprecursors or other chemicals when chemically synthesized. A nucleicacid molecule can be fused to other coding or regulatory sequences andstill be considered “isolated.” Nucleic acid molecules present innon-human transgenic animals, which do not naturally occur in theanimal, are also considered “isolated.” For example, recombinant DNAmolecules contained in a vector are considered “isolated.” Furtherexamples of “isolated” DNA molecules include recombinant DNA moleculesmaintained in heterologous host cells, and purified (partially orsubstantially) DNA molecules in solution. Isolated RNA molecules includein vivo or in vitro RNA transcripts of the isolated SNP-containing DNAmolecules of the present invention. Isolated nucleic acid moleculesaccording to the present invention further include such moleculesproduced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprisesone or more SNP positions disclosed by the present invention withflanking nucleotide sequences on either side of the SNP positions. Aflanking sequence can include nucleotide residues that are naturallyassociated with the SNP site and/or heterologous nucleotide sequences.Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50,30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between)on either side of a SNP position, or as long as the full-length gene orentire protein-coding sequence (or any portion thereof such as an exon),especially if the SNP-containing nucleic acid molecule is to be used toproduce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNPflanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2KB, 1 KB on either side of the SNP. Furthermore, in such instances theisolated nucleic acid molecule comprises exonic sequences (includingprotein-coding and/or non-coding exonic sequences), but may also includeintronic sequences. Thus, any protein coding sequence may be eithercontiguous or separated by introns. The important point is that thenucleic acid is isolated from remote and unimportant flanking sequencesand is of appropriate length such that it can be subjected to thespecific manipulations or uses described herein such as recombinantprotein expression, preparation of probes and primers for assaying theSNP position, and other uses specific to the SNP-containing nucleic acidsequences.

An isolated SNP-containing nucleic acid molecule can comprise, forexample, a full-length gene or transcript, such as a gene isolated fromgenomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, oran mRNA transcript molecule. Polymorphic transcript sequences arereferred to in Table 1 and provided in the Sequence Listing (SEQ IDNOS:1-307), and polymorphic genomic sequences are referred to in Table 2and provided in the Sequence Listing (SEQ ID NOS:1015-1400).Furthermore, fragments of such full-length genes and transcripts thatcontain one or more SNPs disclosed herein are also encompassed by thepresent invention, and such fragments may be used, for example, toexpress any part of a protein, such as a particular functional domain oran antigenic epitope.

Thus, the present invention also encompasses fragments of the nucleicacid sequences as disclosed in Tables 1 and 2 (transcript sequences arereferred to in Table 1 as SEQ ID NOS:1-307, genomic sequences arereferred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNPcontext sequences are referred to in Table 1 as SEQ ID NOS:615-1014, andgenomic-based SNP context sequences are referred to in Table 2 as SEQ IDNOS:1401-4006 and 5414) and their complements. The actual sequencesreferred to in the tables are provided in the Sequence Listing. Afragment typically comprises a contiguous nucleotide sequence at leastabout 8 or more nucleotides, more preferably at least about 12 or morenucleotides, and even more preferably at least about 16 or morenucleotides. Furthermore, a fragment could comprise at least about 18,20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 nucleotides inlength (or any other number in between). The length of the fragment willbe based on its intended use. For example, the fragment can encodeepitope-bearing regions of a variant peptide or regions of a variantpeptide that differ from the normal/wild-type protein, or can be usefulas a polynucleotide probe or primer. Such fragments can be isolatedusing the nucleotide sequences provided in Table 1 and/or Table 2 forthe synthesis of a polynucleotide probe. A labeled probe can then beused, for example, to screen a cDNA library, genomic DNA library, ormRNA to isolate nucleic acid corresponding to the coding region.Further, primers can be used in amplification reactions, such as forpurposes of assaying one or more SNPs sites or for cloning specificregions of a gene.

An isolated nucleic acid molecule of the present invention furtherencompasses a SNP-containing polynucleotide that is the product of anyone of a variety of nucleic acid amplification methods, which are usedto increase the copy numbers of a polynucleotide of interest in anucleic acid sample. Such amplification methods are well known in theart, and they include but are not limited to, polymerase chain reaction(PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology:Principles and Applications for DNA Amplification, ed. H. A. Erlich,Freeman Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu andWallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077(1988)), strand displacement amplification (SDA) (U.S. Pat. Nos.5,270,184 and 5,422,252), transcription-mediated amplification (TMA)(U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat.No. 6,027,923) and the like, and isothermal amplification methods suchas nucleic acid sequence based amplification (NASBA) and self-sustainedsequence replication (Guatelli et al., Proc Natl Acad Sci USA 87:1874(1990)). Based on such methodologies, a person skilled in the art canreadily design primers in any suitable regions 5′ and 3′ to a SNPdisclosed herein. Such primers may be used to amplify DNA of any lengthso long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is aSNP-containing nucleic acid molecule whose amount has been increased atleast two fold by any nucleic acid amplification method performed invitro as compared to its starting amount in a test sample. In otherpreferred embodiments, an amplified polynucleotide is the result of atleast ten fold, fifty fold, one hundred fold, one thousand fold, or eventen thousand fold increase as compared to its starting amount in a testsample. In a typical PCR amplification, a polynucleotide of interest isoften amplified at least fifty thousand fold in amount over theunamplified genomic DNA, but the precise amount of amplification neededfor an assay depends on the sensitivity of the subsequent detectionmethod used.

Generally, an amplified polynucleotide is at least about 16 nucleotidesin length. More typically, an amplified polynucleotide is at least about20 nucleotides in length. In a preferred embodiment of the invention, anamplified polynucleotide is at least about 30 nucleotides in length. Ina more preferred embodiment of the invention, an amplifiedpolynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides inlength. In yet another preferred embodiment of the invention, anamplified polynucleotide is at least about 100, 200, 300, 400, or 500nucleotides in length. While the total length of an amplifiedpolynucleotide of the invention can be as long as an exon, an intron orthe entire gene where the SNP of interest resides, an amplified productis typically up to about 1,000 nucleotides in length (although certainamplification methods may generate amplified products greater than 1000nucleotides in length). More preferably, an amplified polynucleotide isnot greater than about 600-700 nucleotides in length. It is understoodthat irrespective of the length of an amplified polynucleotide, a SNP ofinterest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is atleast about 201 nucleotides in length, comprises one of thetranscript-based context sequences or the genomic-based contextsequences shown in Tables 1 and 2. Such a product may have additionalsequences on its 5′ end or 3′ end or both. In another embodiment, theamplified product is about 101 nucleotides in length, and it contains aSNP disclosed herein. Preferably, the SNP is located at the middle ofthe amplified product (e.g., at position 101 in an amplified productthat is 201 nucleotides in length, or at position 51 in an amplifiedproduct that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplifiedproduct. However, as indicated above, the SNP of interest may be locatedanywhere along the length of the amplified product.

The present invention provides isolated nucleic acid molecules thatcomprise, consist of, or consist essentially of one or morepolynucleotide sequences that contain one or more SNPs disclosed herein,complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules thatconsist of any of the nucleotide sequences shown in Table 1 and/or Table2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307,genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400,transcript-based SNP context sequences are referred to in Table 1 as SEQID NOS:615-1014, and genomic-based SNP context sequences are referred toin Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acidmolecule that encodes any of the variant proteins referred to in Table 1(SEQ ID NOS:308-614). The actual sequences referred to in the tables areprovided in the Sequence Listing. A nucleic acid molecule consists of anucleotide sequence when the nucleotide sequence is the completenucleotide sequence of the nucleic acid molecule.

The present invention further provides nucleic acid molecules thatconsist essentially of any of the nucleotide sequences referred to inTable 1 and/or Table 2 (transcript sequences are referred to in Table 1as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQID NOS:1015-1400, transcript-based SNP context sequences are referred toin Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP contextsequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414),or any nucleic acid molecule that encodes any of the variant proteinsreferred to in Table 1 (SEQ ID NOS:308-614). The actual sequencesreferred to in the tables are provided in the Sequence Listing. Anucleic acid molecule consists essentially of a nucleotide sequence whensuch a nucleotide sequence is present with only a few additionalnucleotide residues in the final nucleic acid molecule.

The present invention further provides nucleic acid molecules thatcomprise any of the nucleotide sequences shown in Table 1 and/or Table 2or a SNP-containing fragment thereof (transcript sequences are referredto in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to inTable 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequencesare referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNPcontext sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and5414), or any nucleic acid molecule that encodes any of the variantproteins provided in Table 1 (SEQ ID NOS:308-614). The actual sequencesreferred to in the tables are provided in the Sequence Listing. Anucleic acid molecule comprises a nucleotide sequence when thenucleotide sequence is at least part of the final nucleotide sequence ofthe nucleic acid molecule. In such a fashion, the nucleic acid moleculecan be only the nucleotide sequence or have additional nucleotideresidues, such as residues that are naturally associated with it orheterologous nucleotide sequences. Such a nucleic acid molecule can haveone to a few additional nucleotides or can comprise many more additionalnucleotides. A brief description of how various types of these nucleicacid molecules can be readily made and isolated is provided below, andsuch techniques are well known to those of ordinary skill in the art.Sambrook and Russell, Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Press, N.Y. (2000).

The isolated nucleic acid molecules can encode mature proteins plusadditional amino or carboxyl-terminal amino acids or both, or aminoacids interior to the mature peptide (when the mature form has more thanone peptide chain, for instance). Such sequences may play a role inprocessing of a protein from precursor to a mature form, facilitateprotein trafficking, prolong or shorten protein half-life, or facilitatemanipulation of a protein for assay or production. As generally is thecase in situ, the additional amino acids may be processed away from themature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limitedto, nucleic acid molecules having a sequence encoding a peptide alone, asequence encoding a mature peptide and additional coding sequences suchas a leader or secretory sequence (e.g., a pre-pro or pro-proteinsequence), a sequence encoding a mature peptide with or withoutadditional coding sequences, plus additional non-coding sequences, forexample introns and non-coding 5′ and 3′ sequences such as transcribedbut untranslated sequences that play a role in, for example,transcription, mRNA processing (including splicing and polyadenylationsignals), ribosome binding, and/or stability of mRNA. In addition, thenucleic acid molecules may be fused to heterologous marker sequencesencoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA,or in the form DNA, including cDNA and genomic DNA, which may beobtained, for example, by molecular cloning or produced by chemicalsynthetic techniques or by a combination thereof. Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y.(2000). Furthermore, isolated nucleic acid molecules, particularly SNPdetection reagents such as probes and primers, can also be partially orcompletely in the form of one or more types of nucleic acid analogs,such as peptide nucleic acid (PNA). U.S. Pat. Nos. 5,539,082; 5,527,675;5,623,049; and 5,714,331. The nucleic acid, especially DNA, can bedouble-stranded or single-stranded. Single-stranded nucleic acid can bethe coding strand (sense strand) or the complementary non-coding strand(anti-sense strand). DNA, RNA, or PNA segments can be assembled, forexample, from fragments of the human genome (in the case of DNA or RNA)or single nucleotides, short oligonucleotide linkers, or from a seriesof oligonucleotides, to provide a synthetic nucleic acid molecule.Nucleic acid molecules can be readily synthesized using the sequencesprovided herein as a reference; oligonucleotide and PNA oligomersynthesis techniques are well known in the art. See, e.g., Corey,“Peptide nucleic acids: expanding the scope of nucleic acidrecognition,” Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup etal., “Peptide nucleic acids (PNA): synthesis, properties and potentialapplications,” Bioorg Med Chem 4(1):5-23) (January 1996). Furthermore,large-scale automated oligonucleotide/PNA synthesis (including synthesison an array or bead surface or other solid support) can readily beaccomplished using commercially available nucleic acid synthesizers,such as the Applied Biosystems (Foster City, Calif.) 3900High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid SynthesisSystem, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that containmodified, synthetic, or non-naturally occurring nucleotides orstructural elements or other alternative/modified nucleic acidchemistries known in the art. Such nucleic acid analogs are useful, forexample, as detection reagents (e.g., primers/probes) for detecting oneor more SNPs identified in Table 1 and/or Table 2. Furthermore,kits/systems (such as beads, arrays, etc.) that include these analogsare also encompassed by the present invention. For example, PNAoligomers that are based on the polymorphic sequences of the presentinvention are specifically contemplated. PNA oligomers are analogs ofDNA in which the phosphate backbone is replaced with a peptide-likebackbone. Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal ChemistryLetters 6:793-796 (1996); Kumar et al., Organic Letters 3(9):1269-1272(2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA withhigher affinity and specificity than conventional oligonucleotides andoligonucleotide analogs. The properties of PNA enable novel molecularbiology and biochemistry applications unachievable with traditionaloligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve thebinding properties and/or stability of a nucleic acid include the use ofbase analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263)and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, referencesherein to nucleic acid molecules, SNP-containing nucleic acid molecules,SNP detection reagents (e.g., probes and primers),oligonucleotides/polynucleotides include PNA oligomers and other nucleicacid analogs. Other examples of nucleic acid analogs andalternative/modified nucleic acid chemistries known in the art aredescribed in Current Protocols in Nucleic Acid Chemistry, John Wiley &Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules thatencode fragments of the variant polypeptides disclosed herein as well asnucleic acid molecules that encode obvious variants of such variantpolypeptides. Such nucleic acid molecules may be naturally occurring,such as paralogs (different locus) and orthologs (different organism),or may be constructed by recombinant DNA methods or by chemicalsynthesis. Non-naturally occurring variants may be made by mutagenesistechniques, including those applied to nucleic acid molecules, cells, ororganisms. Accordingly, the variants can contain nucleotidesubstitutions, deletions, inversions and insertions (in addition to theSNPs disclosed in Tables 1 and 2). Variation can occur in either or boththe coding and non-coding regions. The variations can produceconservative and/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1 and2, such as naturally occurring allelic variants (as well as orthologsand paralogs) and synthetic variants produced by mutagenesis techniques,can be identified and/or produced using methods well known in the art.Such further variants can comprise a nucleotide sequence that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a nucleic acid sequence disclosed in Table 1and/or Table 2 (or a fragment thereof) and that includes a novel SNPallele disclosed in Table 1 and/or Table 2. Further, variants cancomprise a nucleotide sequence that encodes a polypeptide that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a polypeptide sequence disclosed in Table 1(or a fragment thereof) and that includes a novel SNP allele disclosedin Table 1 and/or Table 2. Thus, an aspect of the present invention thatis specifically contemplated are isolated nucleic acid molecules thathave a certain degree of sequence variation compared with the sequencesshown in Tables 1-2, but that contain a novel SNP allele disclosedherein. In other words, as long as an isolated nucleic acid moleculecontains a novel SNP allele disclosed herein, other portions of thenucleic acid molecule that flank the novel SNP allele can vary to somedegree from the specific transcript, genomic, and context sequencesreferred to and shown in Tables 1 and 2, and can encode a polypeptidethat varies to some degree from the specific polypeptide sequencesreferred to in Table 1.

To determine the percent identity of two amino acid sequences or twonucleotide sequences of two molecules that share sequence homology, thesequences are aligned for optimal comparison purposes (e.g., gaps can beintroduced in one or both of a first and a second amino acid or nucleicacid sequence for optimal alignment and non-homologous sequences can bedisregarded for comparison purposes). In a preferred embodiment, atleast 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of areference sequence is aligned for comparison purposes. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”). Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences, taking into account thenumber of gaps, and the length of each gap, which need to be introducedfor optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. Computational Molecular Biology, A. M. Lesk, ed., OxfordUniversity Press, N.Y (1988); Biocomputing: Informatics and GenomeProjects, D. W. Smith, ed., Academic Press, N.Y. (1993); ComputerAnalysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin,eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology,G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence AnalysisPrimer, M. Gribskov and J. Devereux, eds., M. Stockton Press, N.Y.(1991). In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunschalgorithm (J Mol Biol (48):444-453 (1970)) which has been incorporatedinto the GAP program in the GCG software package, using either a Blossom62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6,or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between twonucleotide sequences is determined using the GAP program in the GCGsoftware package using a NWSgapdna.CMP matrix and a gap weight of 40,50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J.Devereux et al., Nucleic Acids Res. 12(1):387 (1984). In anotherembodiment, the percent identity between two amino acid or nucleotidesequences is determined using the algorithm of E. Myers and W. Miller(CABIOS 4:11-17 (1989)) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention canfurther be used as a “query sequence” to perform a search againstsequence databases; for example, to identify other family members orrelated sequences. Such searches can be performed using the NBLAST andXBLAST programs (version 2.0). Altschul et al., J Mol Biol 215:403-10(1990). BLAST nucleotide searches can be performed with the NBLASTprogram, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to the nucleic acid molecules of the invention. BLAST proteinsearches can be performed with the XBLAST program, score=50,wordlength=3 to obtain amino acid sequences homologous to the proteinsof the invention. To obtain gapped alignments for comparison purposes,Gapped BLAST can be utilized. Altschul et al., Nucleic Acids Res25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs,the default parameters of the respective programs (e.g., XBLAST andNBLAST) can be used. In addition to BLAST, examples of other search andsequence comparison programs used in the art include, but are notlimited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) andKERR (Dufresne et al., Nat Biotechnol 20(12):1269-71 (December 2002)).For further information regarding bioinformatics techniques, see CurrentProtocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

The present invention further provides non-coding fragments of thenucleic acid molecules disclosed in Table 1 and/or Table 2. Preferrednon-coding fragments include, but are not limited to, promotersequences, enhancer sequences, intronic sequences, 5′ untranslatedregions (UTRs), 3′ untranslated regions, gene modulating sequences andgene termination sequences. Such fragments are useful, for example, incontrolling heterologous gene expression and in developing screens toidentify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed inTable 1 and/or Table 2, and their associated transcript sequences(referred to in Table 1 as SEQ ID NOS:1-307), genomic sequences(referred to in Table 2 as SEQ ID NOS:1015-1400), and context sequences(transcript-based context sequences are referred to in Table 1 as SEQ IDNOS:615-1014; genomic-based context sequences are provided in Table 2 asSEQ ID NOS:1401-4006 and 5414), can be used for the design of SNPdetection reagents. The actual sequences referred to in the tables areprovided in the Sequence Listing. As used herein, a “SNP detectionreagent” is a reagent that specifically detects a specific target SNPposition disclosed herein, and that is preferably specific for aparticular nucleotide (allele) of the target SNP position (i.e., thedetection reagent preferably can differentiate between differentalternative nucleotides at a target SNP position, thereby allowing theidentity of the nucleotide present at the target SNP position to bedetermined). Typically, such detection reagent hybridizes to a targetSNP-containing nucleic acid molecule by complementary base-pairing in asequence specific manner, and discriminates the target variant sequencefrom other nucleic acid sequences such as an art-known form in a testsample. An example of a detection reagent is a probe that hybridizes toa target nucleic acid containing one or more of the SNPs referred to inTable 1 and/or Table 2. In a preferred embodiment, such a probe candifferentiate between nucleic acids having a particular nucleotide(allele) at a target SNP position from other nucleic acids that have adifferent nucleotide at the same target SNP position. In addition, adetection reagent may hybridize to a specific region 5′ and/or 3′ to aSNP position, particularly a region corresponding to the contextsequences referred to in Table 1 and/or Table 2 (transcript-basedcontext sequences are referred to in Table 1 as SEQ ID NOS:615-1014;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS:1401-4006 and 5414). Another example of a detection reagent is aprimer that acts as an initiation point of nucleotide extension along acomplementary strand of a target polynucleotide. The SNP sequenceinformation provided herein is also useful for designing primers, e.g.allele-specific primers, to amplify (e.g., using PCR) any SNP of thepresent invention.

In one preferred embodiment of the invention, a SNP detection reagent isan isolated or synthetic DNA or RNA polynucleotide probe or primer orPNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizesto a segment of a target nucleic acid molecule containing a SNPidentified in Table 1 and/or Table 2. A detection reagent in the form ofa polynucleotide may optionally contain modified base analogs,intercalators or minor groove binders. Multiple detection reagents suchas probes may be, for example, affixed to a solid support (e.g., arraysor beads) or supplied in solution (e.g. probe/primer sets for enzymaticreactions such as PCR, RT-PCR, TaqMan assays, or primer-extensionreactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotideor PNA oligomer. Such oligonucleotide typically comprises a region ofcomplementary nucleotide sequence that hybridizes under stringentconditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50,55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) ormore consecutive nucleotides in a target nucleic acid molecule.Depending on the particular assay, the consecutive nucleotides caneither include the target SNP position, or be a specific region in closeenough proximity 5′ and/or 3′ to the SNP position to carry out thedesired assay.

Other preferred primer and probe sequences can readily be determinedusing the transcript sequences (SEQ ID NOS:1-307), genomic sequences(SEQ ID NOS:1015-1400), and SNP context sequences (transcript-basedcontext sequences are referred to in Table 1 as SEQ ID NOS:615-1014;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS:1401-4006 and 5414) disclosed in the Sequence Listing and in Tables1 and 2. The actual sequences referred to in the tables are provided inthe Sequence Listing. It will be apparent to one of skill in the artthat such primers and probes are directly useful as reagents forgenotyping the SNPs of the present invention, and can be incorporatedinto any kit/system format.

In order to produce a probe or primer specific for a targetSNP-containing sequence, the gene/transcript and/or context sequencesurrounding the SNP of interest is typically examined using a computeralgorithm that starts at the 5′ or at the 3′ end of the nucleotidesequence. Typical algorithms will then identify oligomers of definedlength that are unique to the gene/SNP context sequence, have a GCcontent within a range suitable for hybridization, lack predictedsecondary structure that may interfere with hybridization, and/orpossess other desired characteristics or that lack other undesiredcharacteristics.

A primer or probe of the present invention is typically at least about 8nucleotides in length. In one embodiment of the invention, a primer or aprobe is at least about 10 nucleotides in length. In a preferredembodiment, a primer or a probe is at least about 12 nucleotides inlength. In a more preferred embodiment, a primer or probe is at leastabout 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length.While the maximal length of a probe can be as long as the targetsequence to be detected, depending on the type of assay in which it isemployed, it is typically less than about 50, 60, 65, or 70 nucleotidesin length. In the case of a primer, it is typically less than about 30nucleotides in length. In a specific preferred embodiment of theinvention, a primer or a probe is within the length of about 18 andabout 28 nucleotides. However, in other embodiments, such as nucleicacid arrays and other embodiments in which probes are affixed to asubstrate, the probes can be longer, such as on the order of 30-70, 75,80, 90, 100, or more nucleotides in length (see the section belowentitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotidesspecific for alternative SNP alleles. Such oligonucleotides that detectsingle nucleotide variations in target sequences may be referred to bysuch terms as “allele-specific oligonucleotides,” “allele-specificprobes,” or “allele-specific primers.” The design and use ofallele-specific probes for analyzing polymorphisms is described in,e.g., Mutation Detection: A Practical Approach, Cotton et al., eds.,Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986);Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends onvariables such as the precise composition of the nucleotide sequencesflanking a SNP position in a target nucleic acid molecule, and thelength of the primer or probe, another factor in the use of primers andprobes is the stringency of the condition under which the hybridizationbetween the probe or primer and the target sequence is performed. Higherstringency conditions utilize buffers with lower ionic strength and/or ahigher reaction temperature, and tend to require a more perfect matchbetween probe/primer and a target sequence in order to form a stableduplex. If the stringency is too high, however, hybridization may notoccur at all. In contrast, lower stringency conditions utilize bufferswith higher ionic strength and/or a lower reaction temperature, andpermit the formation of stable duplexes with more mismatched basesbetween a probe/primer and a target sequence. By way of example and notlimitation, exemplary conditions for high stringency hybridizationconditions using an allele-specific probe are as follows:prehybridization with a solution containing 5× standard saline phosphateEDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe withtarget nucleic acid molecules in the same solution at the sametemperature, followed by washing with a solution containing 2×SSPE, and0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used forallele-specific primer extension reactions with a solution containing,e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may becarried out at an elevated temperature such as 60° C. In anotherembodiment, a moderately stringent hybridization condition suitable foroligonucleotide ligation assay (OLA) reactions wherein two probes areligated if they are completely complementary to the target sequence mayutilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designedthat hybridize to a segment of target DNA from one individual but do nothybridize to the corresponding segment from another individual due tothe presence of different polymorphic forms (e.g., alternative SNPalleles/nucleotides) in the respective DNA segments from the twoindividuals. Hybridization conditions should be sufficiently stringentthat there is a significant detectable difference in hybridizationintensity between alleles, and preferably an essentially binaryresponse, whereby a probe hybridizes to only one of the alleles orsignificantly more strongly to one allele. While a probe may be designedto hybridize to a target sequence that contains a SNP site such that theSNP site aligns anywhere along the sequence of the probe, the probe ispreferably designed to hybridize to a segment of the target sequencesuch that the SNP site aligns with a central position of the probe(e.g., a position within the probe that is at least three nucleotidesfrom either end of the probe). This design of probe generally achievesgood discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize toa segment of target DNA such that the SNP aligns with either the 5′ mostend or the 3′ most end of the probe or primer. In a specific preferredembodiment that is particularly suitable for use in a oligonucleotideligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of theprobe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well knownin the art. Chemical synthetic methods include, but are not limited to,the phosphotriester method described by Narang et al., Methods inEnzymology 68:90 (1979); the phosphodiester method described by Brown etal., Methods in Enzymology 68:109 (1979); the diethylphosphoamidatemethod described by Beaucage et al., Tetrahedron Letters 22:1859 (1981);and the solid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, insets of 3 or 4, such as if a SNP position is known to have 3 or 4alleles, respectively, or to assay both strands of a nucleic acidmolecule for a target SNP allele), and such pairs may be identicalexcept for a one nucleotide mismatch that represents the allelicvariants at the SNP position. Commonly, one member of a pair perfectlymatches a reference form of a target sequence that has a more common SNPallele (i.e., the allele that is more frequent in the target population)and the other member of the pair perfectly matches a form of the targetsequence that has a less common SNP allele (i.e., the allele that israrer in the target population). In the case of an array, multiple pairsof probes can be immobilized on the same support for simultaneousanalysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes toa region on a target nucleic acid molecule that overlaps a SNP positionand only primes amplification of an allelic form to which the primerexhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448(1989). Typically, the primer's 3′-most nucleotide is aligned with andcomplementary to the SNP position of the target nucleic acid molecule.This primer is used in conjunction with a second primer that hybridizesat a distal site. Amplification proceeds from the two primers, producinga detectable product that indicates which allelic form is present in thetest sample. A control is usually performed with a second pair ofprimers, one of which shows a single base mismatch at the polymorphicsite and the other of which exhibits perfect complementarity to a distalsite. The single-base mismatch prevents amplification or substantiallyreduces amplification efficiency, so that either no detectable productis formed or it is formed in lower amounts or at a slower pace. Themethod generally works most effectively when the mismatch is at the3′-most position of the oligonucleotide (i.e., the 3′-most position ofthe oligonucleotide aligns with the target SNP position) because thisposition is most destabilizing to elongation from the primer (see, e.g.,WO 93/22456). This PCR-based assay can be utilized as part of the TaqManassay, described below.

In a specific embodiment of the invention, a primer of the inventioncontains a sequence substantially complementary to a segment of a targetSNP-containing nucleic acid molecule except that the primer has amismatched nucleotide in one of the three nucleotide positions at the3′-most end of the primer, such that the mismatched nucleotide does notbase pair with a particular allele at the SNP site. In a preferredembodiment, the mismatched nucleotide in the primer is the second fromthe last nucleotide at the 3′-most position of the primer. In a morepreferred embodiment, the mismatched nucleotide in the primer is thelast nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of theinvention is labeled with a fluorogenic reporter dye that emits adetectable signal. While the preferred reporter dye is a fluorescentdye, any reporter dye that can be attached to a detection reagent suchas an oligonucleotide probe or primer is suitable for use in theinvention. Such dyes include, but are not limited to, Acridine, AMCA,BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin,Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine,Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may befurther labeled with a quencher dye such as Tamra, especially when thereagent is used as a self-quenching probe such as a TaqMan (U.S. Pat.Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos.5,118,801 and 5,312,728), or other stemless or linear beacon probe(Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., NatureBiotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res25:2516-2521 (1997); U.S. Pat. Nos. 5,866,336 and 6,117,635.

The detection reagents of the invention may also contain other labels,including but not limited to, biotin for streptavidin binding, haptenfor antibody binding, and oligonucleotide for binding to anothercomplementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (orthat are complementary to) a SNP nucleotide identified herein but thatare used to assay one or more SNPs disclosed herein. For example,primers that flank, but do not hybridize directly to a target SNPposition provided herein are useful in primer extension reactions inwhich the primers hybridize to a region adjacent to the target SNPposition (i.e., within one or more nucleotides from the target SNPsite). During the primer extension reaction, a primer is typically notable to extend past a target SNP site if a particular nucleotide(allele) is present at that target SNP site, and the primer extensionproduct can be detected in order to determine which SNP allele ispresent at the target SNP site. For example, particular ddNTPs aretypically used in the primer extension reaction to terminate primerextension once a ddNTP is incorporated into the extension product (aprimer extension product which includes a ddNTP at the 3′-most end ofthe primer extension product, and in which the ddNTP is a nucleotide ofa SNP disclosed herein, is a composition that is specificallycontemplated by the present invention). Thus, reagents that bind to anucleic acid molecule in a region adjacent to a SNP site and that areused for assaying the SNP site, even though the bound sequences do notnecessarily include the SNP site itself, are also contemplated by thepresent invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP andassociated sequence information disclosed herein, detection reagents canbe developed and used to assay any SNP of the present inventionindividually or in combination, and such detection reagents can bereadily incorporated into one of the established kit or system formatswhich are well known in the art. The terms “kits” and “systems,” as usedherein in the context of SNP detection reagents, are intended to referto such things as combinations of multiple SNP detection reagents, orone or more SNP detection reagents in combination with one or more othertypes of elements or components (e.g., other types of biochemicalreagents, containers, packages such as packaging intended for commercialsale, substrates to which SNP detection reagents are attached,electronic hardware components, etc.). Accordingly, the presentinvention further provides SNP detection kits and systems, including butnot limited to, packaged probe and primer sets (e.g. TaqMan probe/primersets), arrays/microarrays of nucleic acid molecules, and beads thatcontain one or more probes, primers, or other detection reagents fordetecting one or more SNPs of the present invention. The kits/systemscan optionally include various electronic hardware components; forexample, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip”systems) provided by various manufacturers typically comprise hardwarecomponents. Other kits/systems (e.g., probe/primer sets) may not includeelectronic hardware components, but may be comprised of, for example,one or more SNP detection reagents (along with, optionally, otherbiochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit typically contains one or moredetection reagents and other components (e.g. a buffer, enzymes such asDNA polymerases or ligases, chain extension nucleotides such asdeoxynucleotide triphosphates, and in the case of Sanger-type DNAsequencing reactions, chain terminating nucleotides, positive controlsequences, negative control sequences, and the like) necessary to carryout an assay or reaction, such as amplification and/or detection of aSNP-containing nucleic acid molecule. A kit may further contain meansfor determining the amount of a target nucleic acid, and means forcomparing the amount with a standard, and can comprise instructions forusing the kit to detect the SNP-containing nucleic acid molecule ofinterest. In one embodiment of the present invention, kits are providedwhich contain the necessary reagents to carry out one or more assays todetect one or more SNPs disclosed herein. In a preferred embodiment ofthe present invention, SNP detection kits/systems are in the form ofnucleic acid arrays, or compartmentalized kits, includingmicrofluidic/lab-on-a-chip systems.

SNP detection kits/systems may contain, for example, one or more probes,or pairs of probes, that hybridize to a nucleic acid molecule at or neareach target SNP position. Multiple pairs of allele-specific probes maybe included in the kit/system to simultaneously assay large numbers ofSNPs, at least one of which is a SNP of the present invention. In somekits/systems, the allele-specific probes are immobilized to a substratesuch as an array or bead. For example, the same substrate can compriseallele-specific probes for detecting at least 1; 10; 100; 1000; 10,000;100,000 (or any other number in-between) or substantially all of theSNPs shown in Table 1 and/or Table 2.

The terms “arrays,” “microarrays,” and “DNA chips” are used hereininterchangeably to refer to an array of distinct polynucleotides affixedto a substrate, such as glass, plastic, paper, nylon or other type ofmembrane, filter, chip, or any other suitable solid support. Thepolynucleotides can be synthesized directly on the substrate, orsynthesized separate from the substrate and then affixed to thesubstrate. In one embodiment, the microarray is prepared and usedaccording to the methods described in Chee et al., U.S. Pat. No.5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., NatBiotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci93:10614-10619 (1996), all of which are incorporated herein in theirentirety by reference. In other embodiments, such arrays are produced bythe methods described by Brown et al., U.S. Pat. No. 5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteoet al., “New chips for molecular biology and diagnostics,” BiotechnolAnnu Rev 8:85-101 (2002); Sosnowski et al., “Active microelectronicarray system for DNA hybridization, genotyping and pharmacogenomicapplications,” Psychiatr Genet. 12(4):181-92 (December 2002); Heller,“DNA microarray technology: devices, systems, and applications,” AnnuRev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al.,“Analysis of SNPs and other genomic variations using gel-based chips,”Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-densitygenechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol77:21-42 (2002).

Any number of probes, such as allele-specific probes, may be implementedin an array, and each probe or pair of probes can hybridize to adifferent SNP position. In the case of polynucleotide probes, they canbe synthesized at designated areas (or synthesized separately and thenaffixed to designated areas) on a substrate using a light-directedchemical process. Each DNA chip can contain, for example, thousands tomillions of individual synthetic polynucleotide probes arranged in agrid-like pattern and miniaturized (e.g., to the size of a dime).Preferably, probes are attached to a solid support in an ordered,addressable array.

A microarray can be composed of a large number of unique,single-stranded polynucleotides, usually either synthetic antisensepolynucleotides or fragments of cDNAs, fixed to a solid support. Typicalpolynucleotides are preferably about 6-60 nucleotides in length, morepreferably about 15-30 nucleotides in length, and most preferably about18-25 nucleotides in length. For certain types of microarrays or otherdetection kits/systems, it may be preferable to use oligonucleotidesthat are only about 7-20 nucleotides in length. In other types ofarrays, such as arrays used in conjunction with chemiluminescentdetection technology, preferred probe lengths can be, for example, about15-80 nucleotides in length, preferably about 50-70 nucleotides inlength, more preferably about 55-65 nucleotides in length, and mostpreferably about 60 nucleotides in length. The microarray or detectionkit can contain polynucleotides that cover the known 5′ or 3′ sequenceof a gene/transcript or target SNP site, sequential polynucleotides thatcover the full-length sequence of a gene/transcript; or uniquepolynucleotides selected from particular areas along the length of atarget gene/transcript sequence, particularly areas corresponding to oneor more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides usedin the microarray or detection kit can be specific to a SNP or SNPs ofinterest (e.g., specific to a particular SNP allele at a target SNPsite, or specific to particular SNP alleles at multiple different SNPsites), or specific to a polymorphic gene/transcript orgenes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on thedifferences in hybridization stability of the probes to perfectlymatched and mismatched target sequence variants. For SNP genotyping, itis generally preferable that stringency conditions used in hybridizationassays are high enough such that nucleic acid molecules that differ fromone another at as little as a single SNP position can be differentiated(e.g., typical SNP hybridization assays are designed so thathybridization will occur only if one particular nucleotide is present ata SNP position, but will not occur if an alternative nucleotide ispresent at that SNP position). Such high stringency conditions may bepreferable when using, for example, nucleic acid arrays ofallele-specific probes for SNP detection. Such high stringencyconditions are described in the preceding section, and are well known tothose skilled in the art and can be found in, for example, CurrentProtocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y.(1989).

In other embodiments, the arrays are used in conjunction withchemiluminescent detection technology. The following patents and patentapplications, which are all hereby incorporated by reference, provideadditional information pertaining to chemiluminescent detection. U.S.patent applications that describe chemiluminescent approaches formicroarray detection: Ser. Nos. 10/620,332 and 10/620,333. U.S. patentsthat describe methods and compositions of dioxetane for performingchemiluminescent detection: U.S. Pat. Nos. 6,124,478; 6,107,024;5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. Andthe U.S. published application that discloses methods and compositionsfor microarray controls: US2002/0110828.

In one embodiment of the invention, a nucleic acid array can comprise anarray of probes of about 15-25 nucleotides in length. In furtherembodiments, a nucleic acid array can comprise any number of probes, inwhich at least one probe is capable of detecting one or more SNPsdisclosed in Table 1 and/or Table 2, and/or at least one probe comprisesa fragment of one of the sequences selected from the group consisting ofthose disclosed in Table 1, Table 2, the Sequence Listing, and sequencescomplementary thereto, said fragment comprising at least about 8consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, morepreferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or moreconsecutive nucleotides (or any other number in-between) and containing(or being complementary to) a novel SNP allele disclosed in Table 1and/or Table 2. In some embodiments, the nucleotide complementary to theSNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of theprobe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of thesubstrate by using a chemical coupling procedure and an ink jetapplication apparatus, as described in PCT application W095/251116(Baldeschweiler et al.) which is incorporated herein in its entirety byreference. In another aspect, a “gridded” array analogous to a dot (orslot) blot may be used to arrange and link cDNA fragments oroligonucleotides to the surface of a substrate using a vacuum system,thermal, UV, mechanical or chemical bonding procedures. An array, suchas those described above, may be produced by hand or by using availabledevices (slot blot or dot blot apparatus), materials (any suitable solidsupport), and machines (including robotic instruments), and may contain8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other numberwhich lends itself to the efficient use of commercially availableinstrumentation.

Using such arrays or other kits/systems, the present invention providesmethods of identifying the SNPs disclosed herein in a test sample. Suchmethods typically involve incubating a test sample of nucleic acids withan array comprising one or more probes corresponding to at least one SNPposition of the present invention, and assaying for binding of a nucleicacid from the test sample with one or more of the probes. Conditions forincubating a SNP detection reagent (or a kit/system that employs one ormore such SNP detection reagents) with a test sample vary. Incubationconditions depend on such factors as the format employed in the assay,the detection methods employed, and the type and nature of the detectionreagents used in the assay. One skilled in the art will recognize thatany one of the commonly available hybridization, amplification and arrayassay formats can readily be adapted to detect the SNPs disclosedherein.

A SNP detection kit/system of the present invention may includecomponents that are used to prepare nucleic acids from a test sample forthe subsequent amplification and/or detection of a SNP-containingnucleic acid molecule. Such sample preparation components can be used toproduce nucleic acid extracts (including DNA and/or RNA), proteins ormembrane extracts from any bodily fluids (such as blood, serum, plasma,urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin,hair, cells (especially nucleated cells), biopsies, buccal swabs ortissue specimens. The test samples used in the above-described methodswill vary based on such factors as the assay format, nature of thedetection method, and the specific tissues, cells or extracts used asthe test sample to be assayed. Methods of preparing nucleic acids,proteins, and cell extracts are well known in the art and can be readilyadapted to obtain a sample that is compatible with the system utilized.Automated sample preparation systems for extracting nucleic acids from atest sample are commercially available, and examples are Qiagen'sBioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparationsystem, and Roche Molecular Systems' COBAS AmpliPrep System.

Another form of kit contemplated by the present invention is acompartmentalized kit. A compartmentalized kit includes any kit in whichreagents are contained in separate containers. Such containers include,for example, small glass containers, plastic containers, strips ofplastic, glass or paper, or arraying material such as silica. Suchcontainers allow one to efficiently transfer reagents from onecompartment to another compartment such that the test samples andreagents are not cross-contaminated, or from one container to anothervessel not included in the kit, and the agents or solutions of eachcontainer can be added in a quantitative fashion from one compartment toanother or to another vessel. Such containers may include, for example,one or more containers which will accept the test sample, one or morecontainers which contain at least one probe or other SNP detectionreagent for detecting one or more SNPs of the present invention, one ormore containers which contain wash reagents (such as phosphate bufferedsaline, Tris-buffers, etc.), and one or more containers which containthe reagents used to reveal the presence of the bound probe or other SNPdetection reagents. The kit can optionally further comprise compartmentsand/or reagents for, for example, nucleic acid amplification or otherenzymatic reactions such as primer extension reactions, hybridization,ligation, electrophoresis (preferably capillary electrophoresis), massspectrometry, and/or laser-induced fluorescent detection. The kit mayalso include instructions for using the kit. Exemplary compartmentalizedkits include microfluidic devices known in the art. See, e.g., Weigl etal., “Lab-on-a-chip for drug development,” Adv Drug Deliv Rev55(3):349-77 (February 2003). In such microfluidic devices, thecontainers may be referred to as, for example, microfluidic“compartments,” “chambers,” or “channels.”

Microfluidic devices, which may also be referred to as “lab-on-a-chip”systems, biomedical micro-electro-mechanical systems (bioMEMs), ormulticomponent integrated systems, are exemplary kits/systems of thepresent invention for analyzing SNPs. Such systems miniaturize andcompartmentalize processes such as probe/target hybridization, nucleicacid amplification, and capillary electrophoresis reactions in a singlefunctional device. Such microfluidic devices typically utilize detectionreagents in at least one aspect of the system, and such detectionreagents may be used to detect one or more SNPs of the presentinvention. One example of a microfluidic system is disclosed in U.S.Pat. No. 5,589,136, which describes the integration of PCR amplificationand capillary electrophoresis in chips. Exemplary microfluidic systemscomprise a pattern of microchannels designed onto a glass, silicon,quartz, or plastic wafer included on a microchip. The movements of thesamples may be controlled by electric, electroosmotic or hydrostaticforces applied across different areas of the microchip to createfunctional microscopic valves and pumps with no moving parts. Varyingthe voltage can be used as a means to control the liquid flow atintersections between the micro-machined channels and to change theliquid flow rate for pumping across different sections of the microchip.See, for example, U.S. Pat. Nos. 6,153,073, Dubrow et al., and6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, forexample, nucleic acid amplification, primer extension, capillaryelectrophoresis, and a detection method such as laser inducedfluorescence detection. In a first step of an exemplary process forusing such an exemplary system, nucleic acid samples are amplified,preferably by PCR. Then, the amplification products are subjected toautomated primer extension reactions using ddNTPs (specific fluorescencefor each ddNTP) and the appropriate oligonucleotide primers to carry outprimer extension reactions which hybridize just upstream of the targetedSNP. Once the extension at the 3′ end is completed, the primers areseparated from the unincorporated fluorescent ddNTPs by capillaryelectrophoresis. The separation medium used in capillary electrophoresiscan be, for example, polyacrylamide, polyethyleneglycol or dextran. Theincorporated ddNTPs in the single nucleotide primer extension productsare identified by laser-induced fluorescence detection. Such anexemplary microchip can be used to process, for example, at least 96 to384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety ofuses, especially for the diagnosis, prognosis, treatment, and preventionof CVD (particularly CHD, such as MI, or hypertension). For example, thenucleic acid molecules of the invention are useful for predicting anindividual's risk for developing CVD (particularly the risk for CHD,especially MI, or hypertension), for prognosing the progression of CVD(e.g., the severity or consequences of CHD, particularly MI, orhypertension) in an individual, in evaluating the likelihood of anindividual who has CVD (or who is at increased risk for CVD) ofresponding to treatment (or prevention) of CVD with a particulartherapeutic agent, and/or predicting the likelihood that the individualwill experience toxicity or other undesirable side effects from atreatment, etc. For example, the nucleic acid molecules are useful ashybridization probes, such as for genotyping SNPs in messenger RNA,transcript, cDNA, genomic DNA, amplified DNA or other nucleic acidmolecules, and for isolating full-length cDNA and genomic clonesencoding the variant peptides disclosed in Table 1 as well as theirorthologs.

A probe can hybridize to any nucleotide sequence along the entire lengthof a nucleic acid molecule referred to in Table 1 and/or Table 2.Preferably, a probe of the present invention hybridizes to a region of atarget sequence that encompasses a SNP position indicated in Table 1and/or Table 2. More preferably, a probe hybridizes to a SNP-containingtarget sequence in a sequence-specific manner such that it distinguishesthe target sequence from other nucleotide sequences which vary from thetarget sequence only by which nucleotide is present at the SNP site.Such a probe is particularly useful for detecting the presence of aSNP-containing nucleic acid in a test sample, or for determining whichnucleotide (allele) is present at a particular SNP site (i.e.,genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining thepresence, level, form, and/or distribution of nucleic acid expression.The nucleic acid whose level is determined can be DNA or RNA.Accordingly, probes specific for the SNPs described herein can be usedto assess the presence, expression and/or gene copy number in a givencell, tissue, or organism. These uses are relevant for diagnosis ofdisorders involving an increase or decrease in gene expression relativeto normal levels. In vitro techniques for detection of mRNA include, forexample, Northern blot hybridizations and in situ hybridizations. Invitro techniques for detecting DNA include Southern blot hybridizationsand in situ hybridizations. Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

Probes can be used as part of a diagnostic test kit for identifyingcells or tissues in which a variant protein is expressed, such as bymeasuring the level of a variant protein-encoding nucleic acid (e.g.,mRNA) in a sample of cells from a subject or determining if apolynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used ashybridization probes to detect the SNPs disclosed herein, therebydetermining whether an individual with the polymorphism(s) is at riskfor developing CVD (or has already developed early stage CVD), or thelikelihood that an individual will respond positively to a treatment(including preventive treatment) for CVD such as a particulartherapeutic agent. Detection of a SNP associated with a diseasephenotype provides a diagnostic tool for an active disease and/orgenetic predisposition to the disease.

Furthermore, the nucleic acid molecules of the invention are thereforeuseful for detecting a gene (gene information is disclosed in Table 2,for example) which contains a SNP disclosed herein and/or products ofsuch genes, such as expressed mRNA transcript molecules (transcriptinformation is disclosed in Table 1, for example), and are thus usefulfor detecting gene expression. The nucleic acid molecules can optionallybe implemented in, for example, an array or kit format for use indetecting gene expression.

The nucleic acid molecules of the invention are also useful as primersto amplify any given region of a nucleic acid molecule, particularly aregion containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful forconstructing recombinant vectors (described in greater detail below).Such vectors include expression vectors that express a portion of, orall of, any of the variant peptide sequences referred to in Table 1.Vectors also include insertion vectors, used to integrate into anothernucleic acid molecule sequence, such as into the cellular genome, toalter in situ expression of a gene and/or gene product. For example, anendogenous coding sequence can be replaced via homologous recombinationwith all or part of the coding region containing one or morespecifically introduced SNPs.

The nucleic acid molecules of the invention are also useful forexpressing antigenic portions of the variant proteins, particularlyantigenic portions that contain a variant amino acid sequence (e.g., anamino acid substitution) caused by a SNP disclosed in Table 1 and/orTable 2.

The nucleic acid molecules of the invention are also useful forconstructing vectors containing a gene regulatory region of the nucleicacid molecules of the present invention.

The nucleic acid molecules of the invention are also useful fordesigning ribozymes corresponding to all, or a part, of an mRNA moleculeexpressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful forconstructing host cells expressing a part, or all, of the nucleic acidmolecules and variant peptides.

The nucleic acid molecules of the invention are also useful forconstructing transgenic animals expressing all, or a part, of thenucleic acid molecules and variant peptides. The production ofrecombinant cells and transgenic animals having nucleic acid moleculeswhich contain the SNPs disclosed in Table 1 and/or Table 2 allows, forexample, effective clinical design of treatment compounds and dosageregimens.

The nucleic acid molecules of the invention are also useful in assaysfor drug screening to identify compounds that, for example, modulatenucleic acid expression.

The nucleic acid molecules of the invention are also useful in genetherapy in patients whose cells have aberrant gene expression. Thus,recombinant cells, which include a patient's cells that have beenengineered ex vivo and returned to the patient, can be introduced intoan individual where the recombinant cells produce the desired protein totreat the individual.

SNP Genotyping Methods

The process of determining which nucleotide(s) is/are present at each ofone or more SNP positions (such as a SNP position disclosed in Table 1and/or Table 2), for either or both alleles, may be referred to by suchphrases as SNP genotyping, determining the “identity” of a SNP,determining the “content” of a SNP, or determining whichnucleotide(s)/allele(s) is/are present at a SNP position. Thus, theseterms can refer to detecting a single allele (nucleotide) at a SNPposition or can encompass detecting both alleles (nucleotides) at a SNPposition (such as to determine the homozygous or heterozygous state of aSNP position). Furthermore, these terms may also refer to detecting anamino acid residue encoded by a SNP (such as alternative amino acidresidues that are encoded by different codons created by alternativenucleotides at a SNP position).

The present invention provides methods of SNP genotyping, such as foruse in evaluating an individual's risk for developing CVD (particularlyCHD, such as MI, or hypertension), for evaluating an individual'sprognosis for disease severity and recovery, for predicting thelikelihood that an individual who has previously had CVD (such as CHD,particularly MI, or hypertension) will have a recurrence of CVD again inthe future, for implementing a preventive or treatment regimen for anindividual based on that individual having an increased susceptibilityfor developing CVD (e.g., increased risk for CHD, particularly MI, orhypertension), in evaluating an individual's likelihood of responding toa therapeutic treatment (particularly for treating or preventing CVD),in selecting a treatment or preventive regimen (e.g., in decidingwhether or not to administer a particular therapeutic agent to anindividual having CVD, or who is at increased risk for developing CVD inthe future), or in formulating or selecting a particular treatment orpreventive regimen such as dosage and/or frequency of administration ofa therapeutic agent or choosing which form/type of a therapeutic agentto be administered, such as a particular pharmaceutical composition orcompound, etc.), determining the likelihood of experiencing toxicity orother undesirable side effects from a treatment, or selectingindividuals for a clinical trial of a therapeutic agent (e.g., selectingindividuals to participate in the trial who are most likely to respondpositively to a therapeutic agent and/or excluding individuals from thetrial who are unlikely to respond positively to a therapeutic agentbased on their SNP genotype(s), or selecting individuals who areunlikely to respond positively to a particular therapeutic agent basedon their SNP genotype(s) to participate in a clinical trial of anothertherapeutic agent that may benefit them), etc.

Nucleic acid samples can be genotyped to determine which allele(s)is/are present at any given genetic region (e.g., SNP position) ofinterest by methods well known in the art. The neighboring sequence canbe used to design SNP detection reagents such as oligonucleotide probes,which may optionally be implemented in a kit format. Exemplary SNPgenotyping methods are described in Chen et al., “Single nucleotidepolymorphism genotyping: biochemistry, protocol, cost and throughput,”Pharmacogenomics J 3(2):77-96 (2003); Kwok et al., “Detection of singlenucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003);Shi, “Technologies for individual genotyping: detection of geneticpolymorphisms in drug targets and disease genes,” Am J Pharmacogenomics2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotidepolymorphisms,” Annu Rev Genomics Hum Genet. 2:235-58 (2001). Exemplarytechniques for high-throughput SNP genotyping are described inMarnellos, “High-throughput SNP analysis for genetic associationstudies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNPgenotyping methods include, but are not limited to, TaqMan assays,molecular beacon assays, nucleic acid arrays, allele-specific primerextension, allele-specific PCR, arrayed primer extension, homogeneousprimer extension assays, primer extension with detection by massspectrometry, pyrosequencing, multiplex primer extension sorted ongenetic arrays, ligation with rolling circle amplification, homogeneousligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reactionsorted on genetic arrays, restriction-fragment length polymorphism,single base extension-tag assays, and the Invader assay. Such methodsmay be used in combination with detection mechanisms such as, forexample, luminescence or chemiluminescence detection, fluorescencedetection, time-resolved fluorescence detection, fluorescence resonanceenergy transfer, fluorescence polarization, mass spectrometry, andelectrical detection.

Various methods for detecting polymorphisms include, but are not limitedto, methods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al.,Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoreticmobility of variant and wild type nucleic acid molecules (Orita et al.,PNAS 86:2766 (1989); Cotton et al., Mutat Res 285:125-144 (1993); andHayashi et al., Genet Anal Tech Appl 9:73-79 (1992)), and assaying themovement of polymorphic or wild-type fragments in polyacrylamide gelscontaining a gradient of denaturant using denaturing gradient gelelectrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequencevariations at specific locations can also be assessed by nucleaseprotection assays such as RNase and S1 protection or chemical cleavagemethods.

In a preferred embodiment, SNP genotyping is performed using the TaqManassay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos.5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of aspecific amplified product during PCR. The TaqMan assay utilizes anoligonucleotide probe labeled with a fluorescent reporter dye and aquencher dye. The reporter dye is excited by irradiation at anappropriate wavelength, it transfers energy to the quencher dye in thesame probe via a process called fluorescence resonance energy transfer(FRET). When attached to the probe, the excited reporter dye does notemit a signal. The proximity of the quencher dye to the reporter dye inthe intact probe maintains a reduced fluorescence for the reporter. Thereporter dye and quencher dye may be at the 5′ most and the 3′ mostends, respectively, or vice versa. Alternatively, the reporter dye maybe at the 5′ or 3′ most end while the quencher dye is attached to aninternal nucleotide, or vice versa. In yet another embodiment, both thereporter and the quencher may be attached to internal nucleotides at adistance from each other such that fluorescence of the reporter isreduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves theprobe, thereby separating the reporter dye and the quencher dye andresulting in increased fluorescence of the reporter. Accumulation of PCRproduct is detected directly by monitoring the increase in fluorescenceof the reporter dye. The DNA polymerase cleaves the probe between thereporter dye and the quencher dye only if the probe hybridizes to thetarget SNP-containing template which is amplified during PCR, and theprobe is designed to hybridize to the target SNP site only if aparticular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determinedusing the SNP and associated nucleic acid sequence information providedherein. A number of computer programs, such as Primer Express (AppliedBiosystems, Foster City, Calif.), can be used to rapidly obtain optimalprimer/probe sets. It will be apparent to one of skill in the art thatsuch primers and probes for detecting the SNPs of the present inventionare useful in, for example, screening for individuals who aresusceptible to developing CVD (particularly CHD, such as MI, orhypertension) and related pathologies, or in screening individuals whohave CVD (or who are susceptible to CVD) for their likelihood ofresponding to a particular treatment (e.g., a particular therapeuticagent). These probes and primers can be readily incorporated into a kitformat. The present invention also includes modifications of the Taqmanassay well known in the art such as the use of Molecular Beacon probes(U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S.Pat. Nos. 5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the presentinvention is the use of two oligonucleotide probes in an OLA (see, e.g.,U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to asegment of a target nucleic acid with its 3′ most end aligned with theSNP site. A second probe hybridizes to an adjacent segment of the targetnucleic acid molecule directly 3′ to the first probe. The two juxtaposedprobes hybridize to the target nucleic acid molecule, and are ligated inthe presence of a linking agent such as a ligase if there is perfectcomplementarity between the 3′ most nucleotide of the first probe withthe SNP site. If there is a mismatch, ligation would not occur. Afterthe reaction, the ligated probes are separated from the target nucleicacid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published internationalpatent applications, which are all hereby incorporated by reference,provide additional information pertaining to techniques for carrying outvarious types of OLA. The following U.S. patents describe OLA strategiesfor performing SNP detection: Nos. 6,027,889; 6,268,148; 5,494,810;5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describe OLAstrategies for performing SNP detection using universal arrays, whereina zipcode sequence can be introduced into one of the hybridizationprobes, and the resulting product, or amplified product, hybridized to auniversal zip code array. U.S. application US01/17329 (and 09/584,905)describes OLA (or LDR) followed by PCR, wherein zipcodes areincorporated into OLA probes, and amplified PCR products are determinedby electrophoretic or universal zipcode array readout. U.S. applications60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods andsoftware for multiplexed SNP detection using OLA followed by PCR,wherein zipcodes are incorporated into OLA probes, and amplified PCRproducts are hybridized with a zipchute reagent, and the identity of theSNP determined from electrophoretic readout of the zipchute. In someembodiments, OLA is carried out prior to PCR (or another method ofnucleic acid amplification). In other embodiments, PCR (or anothermethod of nucleic acid amplification) is carried out prior to OLA.

Another method for SNP genotyping is based on mass spectrometry. Massspectrometry takes advantage of the unique mass of each of the fournucleotides of DNA. SNPs can be unambiguously genotyped by massspectrometry by measuring the differences in the mass of nucleic acidshaving alternative SNP alleles. MALDI-TOF (Matrix Assisted LaserDesorption Ionization—Time of Flight) mass spectrometry technology ispreferred for extremely precise determinations of molecular mass, suchas SNPs. Numerous approaches to SNP analysis have been developed basedon mass spectrometry. Preferred mass spectrometry-based methods of SNPgenotyping include primer extension assays, which can also be utilizedin combination with other approaches, such as traditional gel-basedformats and microarrays.

Typically, the primer extension assay involves designing and annealing aprimer to a template PCR amplicon upstream (5′) from a target SNPposition. A mix of dideoxynucleotide triphosphates (ddNTPs) and/ordeoxynucleotide triphosphates (dNTPs) are added to a reaction mixturecontaining template (e.g., a SNP-containing nucleic acid molecule whichhas typically been amplified, such as by PCR), primer, and DNApolymerase. Extension of the primer terminates at the first position inthe template where a nucleotide complementary to one of the ddNTPs inthe mix occurs. The primer can be either immediately adjacent (i.e., thenucleotide at the 3′ end of the primer hybridizes to the nucleotide nextto the target SNP site) or two or more nucleotides removed from the SNPposition. If the primer is several nucleotides removed from the targetSNP position, the only limitation is that the template sequence betweenthe 3′ end of the primer and the SNP position cannot contain anucleotide of the same type as the one to be detected, or this willcause premature termination of the extension primer. Alternatively, ifall four ddNTPs alone, with no dNTPs, are added to the reaction mixture,the primer will always be extended by only one nucleotide, correspondingto the target SNP position. In this instance, primers are designed tobind one nucleotide upstream from the SNP position (i.e., the nucleotideat the 3′ end of the primer hybridizes to the nucleotide that isimmediately adjacent to the target SNP site on the 5′ side of the targetSNP site). Extension by only one nucleotide is preferable, as itminimizes the overall mass of the extended primer, thereby increasingthe resolution of mass differences between alternative SNP nucleotides.Furthermore, mass-tagged ddNTPs can be employed in the primer extensionreactions in place of unmodified ddNTPs. This increases the massdifference between primers extended with these ddNTPs, thereby providingincreased sensitivity and accuracy, and is particularly useful fortyping heterozygous base positions. Mass-tagging also alleviates theneed for intensive sample-preparation procedures and decreases thenecessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF massspectrometry to determine the identity of the nucleotide present at thetarget SNP position. In one method of analysis, the products from theprimer extension reaction are combined with light absorbing crystalsthat form a matrix. The matrix is then hit with an energy source such asa laser to ionize and desorb the nucleic acid molecules into thegas-phase. The ionized molecules are then ejected into a flight tube andaccelerated down the tube towards a detector. The time between theionization event, such as a laser pulse, and collision of the moleculewith the detector is the time of flight of that molecule. The time offlight is precisely correlated with the mass-to-charge ratio (m/z) ofthe ionized molecule. Ions with smaller m/z travel down the tube fasterthan ions with larger m/z and therefore the lighter ions reach thedetector before the heavier ions. The time-of-flight is then convertedinto a corresponding, and highly precise, m/z. In this manner, SNPs canbe identified based on the slight differences in mass, and thecorresponding time of flight differences, inherent in nucleic acidmolecules having different nucleotides at a single base position. Forfurther information regarding the use of primer extension assays inconjunction with MALDI-TOF mass spectrometry for SNP genotyping, see,e.g., Wise et al., “A standard protocol for single nucleotide primerextension in the human genome using matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry,” Rapid CommunMass Spectrom 17(11):1195-202 (2003).

The following references provide further information describing massspectrometry-based methods for SNP genotyping: Bocker, “SNP and mutationdiscovery using base-specific cleavage and MALDI-TOF mass spectrometry,”Bioinformatics 19 Suppl 1:I44-I53 (July 2003); Storm et al., “MALDI-TOFmass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62(2003); Jurinke et al., “The use of Mass ARRAY technology for highthroughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); andJurinke et al., “Automated genotyping using the DNA MassArraytechnology,” Methods Mol Biol 187:179-92 (2002).

SNPs can also be scored by direct DNA sequencing. A variety of automatedsequencing procedures can be utilized (e.g. Biotechniques 19:448(1995)), including sequencing by mass spectrometry. See, e.g., PCTInternational Publication No. WO 94/16101; Cohen et al., Adv Chromatogr36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol38:147-159 (1993). The nucleic acid sequences of the present inventionenable one of ordinary skill in the art to readily design sequencingprimers for such automated sequencing procedures. Commercialinstrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730,and 3730×1 DNA Analyzers (Foster City, Calif.), is commonly used in theart for automated sequencing.

Other methods that can be used to genotype the SNPs of the presentinvention include single-strand conformational polymorphism (SSCP), anddenaturing gradient gel electrophoresis (DGGE). Myers et al., Nature313:495 (1985). SSCP identifies base differences by alteration inelectrophoretic migration of single stranded PCR products, as describedin Orita et al., Proc. Nat. Acad. Single-stranded PCR products can begenerated by heating or otherwise denaturing double stranded PCRproducts. Single-stranded nucleic acids may refold or form secondarystructures that are partially dependent on the base sequence. Thedifferent electrophoretic mobilities of single-stranded amplificationproducts are related to base-sequence differences at SNP positions. DGGEdifferentiates SNP alleles based on the different sequence-dependentstabilities and melting properties inherent in polymorphic DNA and thecorresponding differences in electrophoretic migration patterns in adenaturing gradient gel. PCR Technology: Principles and Applications forDNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y.(1992).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be usedto score SNPs based on the development or loss of a ribozyme cleavagesite. Perfectly matched sequences can be distinguished from mismatchedsequences by nuclease cleavage digestion assays or by differences inmelting temperature. If the SNP affects a restriction enzyme cleavagesite, the SNP can be identified by alterations in restriction enzymedigestion patterns, and the corresponding changes in nucleic acidfragment lengths determined by gel electrophoresis.

SNP genotyping can include the steps of, for example, collecting abiological sample from a human subject (e.g., sample of tissues, cells,fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA,mRNA or both) from the cells of the sample, contacting the nucleic acidswith one or more primers which specifically hybridize to a region of theisolated nucleic acid containing a target SNP under conditions such thathybridization and amplification of the target nucleic acid regionoccurs, and determining the nucleotide present at the SNP position ofinterest, or, in some assays, detecting the presence or absence of anamplification product (assays can be designed so that hybridizationand/or amplification will only occur if a particular SNP allele ispresent or absent). In some assays, the size of the amplificationproduct is detected and compared to the length of a control sample; forexample, deletions and insertions can be detected by a change in size ofthe amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, asdescribed below. Examples of such applications include, but are notlimited to, SNP-disease association analysis, disease predispositionscreening, disease diagnosis, disease prognosis, disease progressionmonitoring, determining therapeutic strategies based on an individual'sgenotype (“pharmacogenomics”), developing therapeutic agents based onSNP genotypes associated with a disease or likelihood of responding to adrug, stratifying patient populations for clinical trials of atherapeutic, preventive, or diagnostic agent, predicting the likelihoodthat an individual will experience toxic side effects from a therapeuticagent, and human identification applications such as forensics.

Analysis of Genetic Associations between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening,disease prognosis, determining drug responsiveness (pharmacogenomics),drug toxicity screening, and other uses described herein, typicallyrelies on initially establishing a genetic association between one ormore specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies.Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998).Observational studies are most frequently carried out in which theresponse of the patients is not interfered with. The first type ofobservational study identifies a sample of persons in whom the suspectedcause of the disease is present and another sample of persons in whomthe suspected cause is absent, and then the frequency of development ofdisease in the two samples is compared. These sampled populations arecalled cohorts, and the study is a prospective study. The other type ofobservational study is case-control or a retrospective study. In typicalcase-control studies, samples are collected from individuals with thephenotype of interest (cases) such as certain manifestations of adisease, and from individuals without the phenotype (controls) in apopulation (target population) that conclusions are to be drawn from.Then the possible causes of the disease are investigatedretrospectively. As the time and costs of collecting samples incase-control studies are considerably less than those for prospectivestudies, case-control studies are the more commonly used study design ingenetic association studies, at least during the exploration anddiscovery stage.

In both types of observational studies, there may be potentialconfounding factors that should be taken into consideration. Confoundingfactors are those that are associated with both the real cause(s) of thedisease and the disease itself, and they include demographic informationsuch as age, gender, ethnicity as well as environmental factors. Whenconfounding factors are not matched in cases and controls in a study,and are not controlled properly, spurious association results can arise.If potential confounding factors are identified, they should becontrolled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is acertain allele or a SNP or a combination of alleles or a haplotype fromseveral SNPs. Thus, tissue specimens (e.g., whole blood) from thesampled individuals may be collected and genomic DNA genotyped for theSNP(s) of interest. In addition to the phenotypic trait of interest,other information such as demographic (e.g., age, gender, ethnicity,etc.), clinical, and environmental information that may influence theoutcome of the trait can be collected to further characterize and definethe sample set. In many cases, these factors are known to be associatedwith diseases and/or SNP allele frequencies. There are likelygene-environment and/or gene-gene interactions as well. Analysis methodsto address gene-environment and gene-gene interactions (for example, theeffects of the presence of both susceptibility alleles at two differentgenes can be greater than the effects of the individual alleles at twogenes combined) are discussed below.

After all the relevant phenotypic and genotypic information has beenobtained, statistical analyses are carried out to determine if there isany significant correlation between the presence of an allele or agenotype with the phenotypic characteristics of an individual.Preferably, data inspection and cleaning are first performed beforecarrying out statistical tests for genetic association. Epidemiologicaland clinical data of the samples can be summarized by descriptivestatistics with tables and graphs. Data validation is preferablyperformed to check for data completion, inconsistent entries, andoutliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests ifdistributions are not normal) may then be used to check for significantdifferences between cases and controls for discrete and continuousvariables, respectively. To ensure genotyping quality, Hardy-Weinbergdisequilibrium tests can be performed on cases and controls separately.Significant deviation from Hardy-Weinberg equilibrium (HWE) in bothcases and controls for individual markers can be indicative ofgenotyping errors. If HWE is violated in a majority of markers, it isindicative of population substructure that should be furtherinvestigated. Moreover, Hardy-Weinberg disequilibrium in cases only canindicate genetic association of the markers with the disease. B. Weir,Genetic Data Analysis, Sinauer (1990).

To test whether an allele of a single SNP is associated with the case orcontrol status of a phenotypic trait, one skilled in the art can compareallele frequencies in cases and controls. Standard chi-squared tests andFisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2outcomes in the categorical trait of interest). To test whethergenotypes of a SNP are associated, chi-squared tests can be carried outon a 3×2 table (3 genotypes×2 outcomes). Score tests are also carriedout for genotypic association to contrast the three genotypicfrequencies (major homozygotes, heterozygotes and minor homozygotes) incases and controls, and to look for trends using 3 different modes ofinheritance, namely dominant (with contrast coefficients 2, −1, −1),additive or allelic (with contrast coefficients 1, 0, −1) and recessive(with contrast coefficients 1, 1, −2). Odds ratios for minor versusmajor alleles, and odds ratios for heterozygote and homozygote variantsversus the wild type genotypes are calculated with the desiredconfidence limits, usually 95%.

In order to control for confounders and to test for interaction andeffect modifiers, stratified analyses may be performed using stratifiedfactors that are likely to be confounding, including demographicinformation such as age, ethnicity, and gender, or an interactingelement or effect modifier, such as a known major gene (e.g., APOE forAlzheimer's disease or HLA genes for autoimmune diseases), orenvironmental factors such as smoking in lung cancer. Stratifiedassociation tests may be carried out using Cochran-Mantel-Haenszel teststhat take into account the ordinal nature of genotypes with 0, 1, and 2variant alleles. Exact tests by StatXact may also be performed whencomputationally possible. Another way to adjust for confounding effectsand test for interactions is to perform stepwise multiple logisticregression analysis using statistical packages such as SAS or R.Logistic regression is a model-building technique in which the bestfitting and most parsimonious model is built to describe the relationbetween the dichotomous outcome (for instance, getting a certain diseaseor not) and a set of independent variables (for instance, genotypes ofdifferent associated genes, and the associated demographic andenvironmental factors). The most common model is one in which the logittransformation of the odds ratios is expressed as a linear combinationof the variables (main effects) and their cross-product terms(interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley(2000). To test whether a certain variable or interaction issignificantly associated with the outcome, coefficients in the model arefirst estimated and then tested for statistical significance of theirdeparture from zero.

In addition to performing association tests one marker at a time,haplotype association analysis may also be performed to study a numberof markers that are closely linked together. Haplotype association testscan have better power than genotypic or allelic association tests whenthe tested markers are not the disease-causing mutations themselves butare in linkage disequilibrium with such mutations. The test will even bemore powerful if the disease is indeed caused by a combination ofalleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs thatare very close to each other). In order to perform haplotype associationeffectively, marker-marker linkage disequilibrium measures, both D′ andr², are typically calculated for the markers within a gene to elucidatethe haplotype structure. Recent studies in linkage disequilibriumindicate that SNPs within a gene are organized in block pattern, and ahigh degree of linkage disequilibrium exists within blocks and verylittle linkage disequilibrium exists between blocks. Daly et al, NatureGenetics 29:232-235 (2001). Haplotype association with the diseasestatus can be performed using such blocks once they have beenelucidated.

Haplotype association tests can be carried out in a similar fashion asthe allelic and genotypic association tests. Each haplotype in a gene isanalogous to an allele in a multi-allelic marker. One skilled in the artcan either compare the haplotype frequencies in cases and controls ortest genetic association with different pairs of haplotypes. It has beenproposed that score tests can be done on haplotypes using the program“haplo.score.” Schaid et al, Am J Hum Genet 70:425-434 (2002). In thatmethod, haplotypes are first inferred by EM algorithm and score testsare carried out with a generalized linear model (GLM) framework thatallows the adjustment of other factors.

An important decision in the performance of genetic association tests isthe determination of the significance level at which significantassociation can be declared when the P value of the tests reaches thatlevel. In an exploratory analysis where positive hits will be followedup in subsequent confirmatory testing, an unadjusted P value <0.2 (asignificance level on the lenient side), for example, may be used forgenerating hypotheses for significant association of a SNP with certainphenotypic characteristics of a disease. It is preferred that a p-value<0.05 (a significance level traditionally used in the art) is achievedin order for a SNP to be considered to have an association with adisease. It is more preferred that a p-value <0.01 (a significance levelon the stringent side) is achieved for an association to be declared.When hits are followed up in confirmatory analyses in more samples ofthe same source or in different samples from different sources,adjustment for multiple testing will be performed as to avoid excessnumber of hits while maintaining the experiment-wide error rates at0.05. While there are different methods to adjust for multiple testingto control for different kinds of error rates, a commonly used butrather conservative method is Bonferroni correction to control theexperiment-wise or family-wise error rate. Westfall et al., Multiplecomparisons and multiple tests, SAS Institute (1999). Permutation teststo control for the false discovery rates, FDR, can be more powerful.Benjamini and Hochberg, Journal of the Royal Statistical Society, SeriesB 57:1289-1300 (1995); Westfall and Young, Resampling-based MultipleTesting, Wiley (1993). Such methods to control for multiplicity would bepreferred when the tests are dependent and controlling for falsediscovery rates is sufficient as opposed to controlling for theexperiment-wise error rates.

In replication studies using samples from different populations afterstatistically significant markers have been identified in theexploratory stage, meta-analyses can then be performed by combiningevidence of different studies. Modern Epidemiology 643-673, Lippincott,Williams & Wilkins (1998). If available, association results known inthe art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involveerrors, sensitivity analyses may be performed to see how odds ratios andp-values would change upon various estimates on genotyping and diseaseclassification error rates.

It has been well known that subpopulation-based sampling bias betweencases and controls can lead to spurious results in case-controlassociation studies when prevalence of the disease is associated withdifferent subpopulation groups. Ewens and Spielman, Am J Hum Genet62:450-458 (1995). Such bias can also lead to a loss of statisticalpower in genetic association studies. To detect populationstratification, Pritchard and Rosenberg suggested typing markers thatare unlinked to the disease and using results of association tests onthose markers to determine whether there is any populationstratification. Pritchard et al., Am J Hum Gen 65:220-228 (1999). Whenstratification is detected, the genomic control (GC) method as proposedby Devlin and Roeder can be used to adjust for the inflation of teststatistics due to population stratification. Devlin et al., Biometrics55:997-1004 (1999). The GC method is robust to changes in populationstructure levels as well as being applicable to DNA pooling designs.Devlin et al., Genet Epidem 21:273-284 (2001).

While Pritchard's method recommended using 15-20 unlinked microsatellitemarkers, it suggested using more than 30 biallelic markers to get enoughpower to detect population stratification. For the GC method, it hasbeen shown that about 60-70 biallelic markers are sufficient to estimatethe inflation factor for the test statistics due to populationstratification. Bacanu et al., Am J Hum Genet 66:1933-1944 (2000).Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicatedin a genome scan. Kehoe et al., Hum Mol Genet 8:237-245 (1999).

Once individual risk factors, genetic or non-genetic, have been foundfor the predisposition to disease, the next step is to set up aclassification/prediction scheme to predict the category (for instance,disease or no-disease) that an individual will be in depending on hisgenotypes of associated SNPs and other non-genetic risk factors.Logistic regression for discrete trait and linear regression forcontinuous trait are standard techniques for such tasks. Draper andSmith, Applied Regression Analysis, Wiley (1998). Moreover, othertechniques can also be used for setting up classification. Suchtechniques include, but are not limited to, MART, CART, neural network,and discriminant analyses that are suitable for use in comparing theperformance of different methods. The Elements of Statistical Learning,Hastie, Tibshirani & Friedman, Springer (2002).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes anddisease-related phenotypes can be exploited in several ways. Forexample, in the case of a highly statistically significant associationbetween one or more SNPs with predisposition to a disease for whichtreatment is available, detection of such a genotype pattern in anindividual may justify immediate administration of treatment, or atleast the institution of regular monitoring of the individual. Detectionof the susceptibility alleles associated with serious disease in acouple contemplating having children may also be valuable to the couplein their reproductive decisions. In the case of a weaker but stillstatistically significant association between a SNP and a human disease,immediate therapeutic intervention or monitoring may not be justifiedafter detecting the susceptibility allele or SNP. Nevertheless, thesubject can be motivated to begin simple life-style changes (e.g., diet,exercise) that can be accomplished at little or no cost to theindividual but would confer potential benefits in reducing the risk ofdeveloping conditions for which that individual may have an increasedrisk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to the development of CVD(e.g., CHD, such as MI, or hypertension), or to responsiveness of anindividual to a therapeutic treatment, in different ways. Somepolymorphisms occur within a protein coding sequence and contribute todisease phenotype by affecting protein structure. Other polymorphismsoccur in noncoding regions but may exert phenotypic effects indirectlyvia influence on, for example, replication, transcription, and/ortranslation. A single SNP may affect more than one phenotypic trait.Likewise, a single phenotypic trait may be affected by multiple SNPs indifferent genes.

As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics”include, but are not limited to, any of the following: detection of CVD(such as CHD, e.g. MI, or hypertension) that an individual may presentlyhave, predisposition/susceptibility/predictive screening (i.e.,determining whether an individual has an increased or decreased risk ofdeveloping CVD in the future), prognosing the future course of CVD orrecurrence of CVD in an individual, determining a particular type orsubclass of CVD in an individual who currently or previously had CVD,confirming or reinforcing a previously made diagnosis of CVD, evaluatingan individual's likelihood of responding positively to a particulartreatment or therapeutic agent (particularly treatment or prevention ofCVD), determining or selecting a therapeutic or preventive strategy thatan individual is most likely to positively respond to (e.g., selecting aparticular therapeutic agent or combination of therapeutic agents, ordetermining a dosing regimen, etc.), classifying (orconfirming/reinforcing) an individual as a responder/non-responder (ordetermining a particular subtype of responder/non-responder) withrespect to the individual's response to a drug treatment, and predictingwhether a patient is likely to experience toxic effects from aparticular treatment or therapeutic compound. Such diagnostic uses canbe based on the SNPs individually or in a unique combination or SNPhaplotypes of the present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs canbe genotyped to determine if a particular genomic region harbors a locusthat influences a particular phenotype, such as in linkagedisequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles(e.g., alternative nucleotides) at two or more different SNP sites atfrequencies greater than would be expected from the separate frequenciesof occurrence of each allele in a given population. The expectedfrequency of co-occurrence of two alleles that are inheritedindependently is the frequency of the first allele multiplied by thefrequency of the second allele. Alleles that co-occur at expectedfrequencies are said to be in “linkage equilibrium.” In contrast, LDrefers to any non-random genetic association between allele(s) at two ormore different SNP sites, which is generally due to the physicalproximity of the two loci along a chromosome. LD can occur when two ormore SNPs sites are in close physical proximity to each other on a givenchromosome and therefore alleles at these SNP sites will tend to remainunseparated for multiple generations with the consequence that aparticular nucleotide (allele) at one SNP site will show a non-randomassociation with a particular nucleotide (allele) at a different SNPsite located nearby. Hence, genotyping one of the SNP sites will givealmost the same information as genotyping the other SNP site that is inLD.

Various degrees of LD can be encountered between two or more SNPs withthe result being that some SNPs are more closely associated (i.e., instronger LD) than others. Furthermore, the physical distance over whichLD extends along a chromosome differs between different regions of thegenome, and therefore the degree of physical separation between two ormore SNP sites necessary for LD to occur can differ between differentregions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site isfound to be useful for, for example, predicting an individual'ssusceptibility to CVD or an individual's response to a treatment, thenthe skilled artisan would recognize that other SNP sites which are in LDwith this SNP site would also be useful for the same purposes. Thus,polymorphisms (e.g., SNPs and/or haplotypes) that are not the actualdisease-causing (causative) polymorphisms, but are in LD with suchcausative polymorphisms, are also useful. In such instances, thegenotype of the polymorphism(s) that is/are in LD with the causativepolymorphism is predictive of the genotype of the causative polymorphismand, consequently, predictive of the phenotype (e.g., CVD, orresponder/non-responder to a drug treatment) that is influenced by thecausative SNP(s). Therefore, polymorphic markers that are in LD withcausative polymorphisms are useful as diagnostic markers, and areparticularly useful when the actual causative polymorphism(s) is/areunknown.

Examples of polymorphisms that can be in LD with one or more causativepolymorphisms (and/or in LD with one or more polymorphisms that have asignificant statistical association with a condition) and thereforeuseful for diagnosing the same condition that the causative/associatedSNP(s) is used to diagnose, include other SNPs in the same gene,protein-coding, or mRNA transcript-coding region as thecausative/associated SNP, other SNPs in the same exon or same intron asthe causative/associated SNP, other SNPs in the same haplotype block asthe causative/associated SNP, other SNPs in the same intergenic regionas the causative/associated SNP, SNPs that are outside but near a gene(e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) thatharbors a causative/associated SNP, etc. Such useful LD SNPs can beselected from among the SNPs disclosed in Tables 1 and 2, for example.

Linkage disequilibrium in the human genome is reviewed in Wall et al.,“Haplotype blocks and linkage disequilibrium in the human genome,” NatRev Genet. 4(8):587-97 (August 2003); Garner et al., “On selectingmarkers for association studies: patterns of linkage disequilibriumbetween two and three diallelic loci,” Genet Epidemiol 24(1):57-67(January 2003); Ardlie et al., “Patterns of linkage disequilibrium inthe human genome,” Nat Rev Genet. 3(4):299-309 (April 2002); erratum inNat Rev Genet 3(7):566 (July 2002); and Remm et al., “High-densitygenotyping and linkage disequilibrium in the human genome usingchromosome 22 as a model,” Curr Opin Chem Biol 6(1):24-30 (Feb. 2002);J. B. S. Haldane, “The combination of linkage values, and thecalculation of distances between the loci of linked factors,” J Genet8:299-309 (1919); G. Mendel, Versuche über Pflanzen-Hybriden.Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of theNatural History Society of Brünn) (1866); Genes IV, B. Lewin, ed.,Oxford University Press, N.Y. (1990); D. L. Hartl and A. G. ClarkPrinciples of Population Genetics 2^(nd) ed., Sinauer Associates, Inc.,Mass. (1989); J. H. Gillespie Population Genetics: A Concise Guide.2^(nd) ed., Johns Hopkins University Press (2004); R. C. Lewontin, “Theinteraction of selection and linkage. I. General considerations;heterotic models,” Genetics 49:49-67 (1964); P. G. Hoel, Introduction toMathematical Statistics 2^(nd) ed., John Wiley & Sons, Inc., N.Y.(1954); R. R. Hudson, “Two-locus sampling distributions and theirapplication,” Genetics 159:1805-1817 (2001); A. P. Dempster, N. M.Laird, D. B. Rubin, “Maximum likelihood from incomplete data via the EMalgorithm,” J R Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin,“Maximum-likelihood estimation of molecular haplotype frequencies in adiploid population,” Mol Biol Evol 12(5):921-927 (1995); D. A. Tregouet,S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, “A new algorithm forhaplotype-based association analysis: the Stochastic-EM algorithm,” AnnHum Genet 68(Pt 2):165-177 (2004); A. D. Long and C. H. Langley C H,“The power of association studies to detect the contribution ofcandidate genetic loci to variation in complex traits,” Genome Research9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley &Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methodsfor Genetic Analysis, Springer-Verlag New York, Inc., N.Y. (1997); TheInternational HapMap Consortium, “The International HapMap Project,”Nature 426:789-796 (2003); The International HapMap Consortium, “Ahaplotype map of the human genome,” Nature 437:1299-1320 (2005); G. A.Thorisson, A. V. Smith, L. Krishnan, L. D. Stein, “The InternationalHapMap Project Web Site,” Genome Research 15:1591-1593 (2005); G.McVean, C. C. A. Spencer, R. Chaix, “Perspectives on human geneticvariation from the HapMap project,” PLoS Genetics 1(4):413-418 (2005);J. N. Hirschhorn, M. J. Daly, “Genome-wide association studies forcommon diseases and complex traits,” Nat Genet 6:95-108 (2005); S. J.Schrodi, “A probabilistic approach to large-scale association scans: asemi-Bayesian method to detect disease-predisposing alleles,” SAGMB4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A. Todd,“Genome-wide association studies: theoretical and practical concerns,”Nat Rev Genet 6:109-118 (2005); J. K. Pritchard, M. Przeworski, “Linkagedisequilibrium in humans: models and data,” Am J Hum Genet 69:1-14(2001).

As discussed above, one aspect of the present invention is the discoverythat SNPs that are in certain LD distance with an interrogated SNP canalso be used as valid markers for determining whether an individual hasan increased or decreased risk of having or developing CVD, for example.As used herein, the term “interrogated SNP” refers to SNPs that havebeen found to be associated with an increased or decreased risk ofdisease using genotyping results and analysis, or other appropriateexperimental method as exemplified in the working examples described inthis application. As used herein, the term “LD SNP” refers to a SNP thathas been characterized as a SNP associating with an increased ordecreased risk of diseases due to their being in LD with the“interrogated SNP” under the methods of calculation described in theapplication. Below, applicants describe the methods of calculation withwhich one of ordinary skilled in the art may determine if a particularSNP is in LD with an interrogated SNP. The parameter r² is commonly usedin the genetics art to characterize the extent of linkage disequilibriumbetween markers (Hudson, 2001). As used herein, the term “in LD with”refers to a particular SNP that is measured at above the threshold of aparameter such as r² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sampleof chromosomes obtained from a population. Suppose one has genotype dataat two genetic markers located on the same chromosome, for the markers Aand B. Further suppose that two alleles segregate at each of these twomarkers such that alleles A₁ and A₂ can be found at marker A and allelesB₁ and B₂ at marker B. Also assume that these two markers are on a humanautosome. If one is to examine a specific individual and find that theyare heterozygous at both markers, such that their two-marker genotype isA₁A₂B₁B₂, then there are two possible configurations: the individual inquestion could have the alleles A₁B₁ on one chromosome and A₂B₂ on theremaining chromosome; alternatively, the individual could have allelesA₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleleson a chromosome is called a haplotype. In this illustration, theindividual could have haplotypes A₁B₁/A₂B₂ or A₁B₂/A₂B₁ (see Hartl andClark (1989) for a more complete description). The concept of linkageequilibrium relates the frequency of haplotypes to the allelefrequencies.

Assume that a sample of individuals is selected from a largerpopulation. Considering the two markers described above, each having twoalleles, there are four possible haplotypes: A₁B₁, A₁B₂, A₂B₁ and A₂B₂.Denote the frequencies of these four haplotypes with the followingnotation.

P _(it)=freq(A ₁ B ₁)  (1)

P ₁₂=freq(A ₁ B ₂)  (2)

P ₂₁=freq(A ₂ B ₁)  (3)

P ₂₂=freq(A ₂ B ₂)  (4)

The allele frequencies at the two markers are then the sum of differenthaplotype frequencies, it is straightforward to write down a similar setof equations relating single-marker allele frequencies to two-markerhaplotype frequencies:

p ₁=freq(A ₁)=P ₁₁ +P ₁₂  (5)

p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6)

q ₁=freq(B ₁)=P ₁₁ +P ₂₁  (7)

q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8)

Note that the four haplotype frequencies and the allele frequencies ateach marker must sum to a frequency of 1.

P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9)

p ₁ +p ₂=1(10)

q ₁ +q ₂=1  (11)

If there is no correlation between the alleles at the two markers, onewould expect that the frequency of the haplotypes would be approximatelythe product of the composite alleles. Therefore,

P ₁₁ ≈p ₁ q ₁  (12)

P ₁₂ ≈p ₁ q ₂  (13)

P ₂₁ ≈p ₂ q ₁  (14)

P ₂₂ ≈p ₂ q ₂  (15)

These approximating equations (12)-(15) represent the concept of linkageequilibrium where there is independent assortment between the twomarkers—the alleles at the two markers occur together at random. Theseare represented as approximations because linkage equilibrium andlinkage disequilibrium are concepts typically thought of as propertiesof a sample of chromosomes; and as such they are susceptible tostochastic fluctuations due to the sampling process. Empirically, manypairs of genetic markers will be in linkage equilibrium, but certainlynot all pairs.

Having established the concept of linkage equilibrium above, applicantscan now describe the concept of linkage disequilibrium (LD), which isthe deviation from linkage equilibrium. Since the frequency of the A₁B₁haplotype is approximately the product of the allele frequencies for A₁and B₁ under the assumption of linkage equilibrium as statedmathematically in (12), a simple measure for the amount of departurefrom linkage equilibrium is the difference in these two quantities, D,

D=P ₁ P ₁₁ −p ₁ q ₁  (16)

D=0 indicates perfect linkage equilibrium. Substantial departures fromD=0 indicates LD in the sample of chromosomes examined. Many propertiesof D are discussed in Lewontin (1964) including the maximum and minimumvalues that D can take. Mathematically, using basic algebra, it can beshown that D can also be written solely in terms of haplotypes:

D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁  (17)

If one transforms D by squaring it and subsequently dividing by theproduct of the allele frequencies of A₁, A₂, B₁ and B₂, the resultingquantity, called r², is equivalent to the square of the Pearson'scorrelation coefficient commonly used in statistics (e.g. Hoel, 1954).

$\begin{matrix}{r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18)\end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium betweenthe two markers examined in the sample set. As values of r² increase,the two markers are said to be in linkage disequilibrium. The range ofvalues that r² can take are from 0 to 1. r²=1 when there is a perfectcorrelation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And assuch, it is necessary to formulate notation specific to the samplesstudied. In the approach discussed here, three types of samples are ofprimary interest: (i) a sample of chromosomes from individuals affectedby a disease-related phenotype (cases), (ii) a sample of chromosomesobtained from individuals not affected by the disease-related phenotype(controls), and (iii) a standard sample set used for the construction ofhaplotypes and calculation pairwise linkage disequilibrium. For theallele frequencies used in the development of the method describedbelow, an additional subscript will be added to denote either the caseor control sample sets.

p _(1,cs)=freq(A ₁ in cases)  (19)

p _(2,cs)=freq(A ₂ in cases)  (20)

q _(1,cs)=freq(B ₁ in cases)  (21)

q _(2,cs)=freq(B ₂ in cases)  (22)

Similarly,

p _(1,ct)=freq(A ₁ in controls)  (23)

p _(2,ct)=freq(A ₂ in controls)  (24)

q _(1,ct)=freq(B ₁ in controls)  (25)

q _(2,ct)=freq(B ₂ in controls)  (26)

As a well-accepted sample set is necessary for robust linkagedisequilibrium calculations, data obtained from the International HapMapproject (The International HapMap Consortium 2003, 2005; Thorisson etal, 2005; McVean et al, 2005) can be used for the calculation ofpairwise r² values. Indeed, the samples genotyped for the InternationalHapMap Project were selected to be representative examples from varioushuman sub-populations with sufficient numbers of chromosomes examined todraw meaningful and robust conclusions from the patterns of geneticvariation observed. The International HapMap project website(hapmap.org) contains a description of the project, methods utilized andsamples examined. It is useful to examine empirical data to get a senseof the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above.However, knowing the 2-marker haplotype frequencies requires that phaseto be determined for doubly heterozygous samples. When phase is unknownin the data examined, various algorithms can be used to infer phase fromthe genotype data. This issue was discussed earlier where the doublyheterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have oneof two different sets of chromosomes: A₁/B₁/A₂B₂ or B₂/A₂B₁. One suchalgorithm to estimate haplotype frequencies is theexpectation-maximization (EM) algorithm first formalized by Dempster etal. (1977). This algorithm is often used in genetics to infer haplotypefrequencies from genotype data (e.g. Excoffier and Slatkin (1995);Tregouet et al. (2004)). It should be noted that for the two-SNP caseexplored here, EM algorithms have very little error provided that theallele frequencies and sample sizes are not too small. The impact on r²values is typically negligible.

As correlated genetic markers share information, interrogation of SNPmarkers in LD with a disease-associated SNP marker can also havesufficient power to detect disease association (Long and Langley(1999)). The relationship between the power to directly finddisease-associated alleles and the power to indirectly detectdisease-association was investigated by Pritchard and Przeworski (2001).In a straight-forward derivation, it can be shown that the power todetect disease association indirectly at a marker locus in linkagedisequilibrium with a disease-association locus is approximately thesame as the power to detect disease-association directly at thedisease-association locus if the sample size is increased by a factor of

$\frac{1}{r^{2}}$

(the reciprocal of equation 18) at the marker in comparison with thedisease-association locus.

Therefore, if one calculated the power to detect disease-associationindirectly with an experiment having N samples, then equivalent power todirectly detect disease-association (at the actualdisease-susceptibility locus) would necessitate an experiment usingapproximately r²N samples. This elementary relationship between power,sample size and linkage disequilibrium can be used to derive an r²threshold value useful in determining whether or not genotyping markersin linkage disequilibrium with a SNP marker directly associated withdisease status has enough power to indirectly detectdisease-association.

To commence a derivation of the power to detect disease-associatedmarkers through an indirect process, define the effective chromosomalsample size as

$\begin{matrix}{{n = \frac{4N_{cs}N_{ct}}{N_{cs} + N_{ct}}};} & (27)\end{matrix}$

where N_(cs) and N_(ct) are the numbers of diploid cases and controls,respectively. This is necessary to handle situations where the numbersof cases and controls are not equivalent. For equal case and controlsample sizes, N_(cs)=N_(ct)=N, the value of the effective number ofchromosomes is simply n=2N—as expected. Let power be calculated for asignificance level α (such that traditional P-values below α will bedeemed statistically significant). Define the standard Gaussiandistribution function as Φ(.). Mathematically,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{\sqrt{2\pi}}{\int_{- \infty}^{x}{^{- \frac{\theta^{2}}{2}}\ {\theta}}}}} & (28)\end{matrix}$

Alternatively, the following error function notation (Erf) may also beused,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{2}\left\lbrack {1 + {{Erf}\left( \frac{x}{\sqrt{2}} \right)}} \right\rbrack}} & (29)\end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield apre-specified minimum amount of power to detect disease associationthough indirect interrogation. Noting that the LD SNP marker could bethe one that is carrying the disease-association allele, therefore thatthis approach constitutes a lower-bound model where all indirect powerresults are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associatedmarkers. Therefore, 1−β is the classical definition of statisticalpower. Substituting the Pritchard-Pzreworski result into the samplesize, the power to detect disease association at a significance level ofα is given by the approximation

$\begin{matrix}{{{1 - \beta} \cong {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - \frac{\alpha}{2}}} \right\rbrack}};} & (30)\end{matrix}$

where Z_(u) is the inverse of the standard normal cumulativedistribution evaluated at u (uε(0,1)). Z_(u)=Φ⁻¹(u), whereΦ(Φ⁻¹(u))=(Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore1−α/2=0.975, one obtains Z_(0.975)=1.95996. Next, setting power equal toa threshold of a minimum power of T,

$\begin{matrix}{T = {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - \frac{\alpha}{2}}} \right\rbrack}} & (31)\end{matrix}$

and solving for r², the following threshold r² is obtained:

$\begin{matrix}{{r_{T}^{2} = {\frac{\left\lbrack {{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}} \right\rbrack}{{n\left( {q_{1,{cs}} - q_{1,{ct}}} \right)}^{2}}\left\lbrack {{\Phi^{- 1}(T)} + Z_{1 - \frac{\alpha}{2}}} \right\rbrack}^{2}}{{Or},}} & (32) \\{r_{T}^{2} = {\frac{\left( {Z_{T} + Z_{1 + \frac{\alpha}{2}}} \right)^{2}}{n}\left\lbrack \frac{q_{1,{cs}} - \left( q_{1,{cs}} \right)^{2} + q_{1,{ct}} - \left( q_{1,{ct}} \right)^{2}}{\left( {q_{1,{cs}} - q_{q,{ct}}} \right)^{2}} \right\rbrack}} & (33)\end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a numberof other SNPs with varying levels of LD with the interrogated SNP. Thethreshold value r_(T) ² is the minimum value of linkage disequilibriumbetween the interrogated SNP and the potential LD SNPs such that the LDSNP still retains a power greater or equal to T for detectingdisease-association. For example, suppose that SNP rs200 is genotyped ina case-control disease-association study and it is found to beassociated with a disease phenotype. Further suppose that the minorallele frequency in 1,000 case chromosomes was found to be 16% incontrast with a minor allele frequency of 10% in 1,000 controlchromosomes. Given those measurements one could have predicted, prior tothe experiment, that the power to detect disease association at asignificance level of 0.05 was quite high—approximately 98% using a testof allelic association. Applying equation (32) one can calculate aminimum value of r² to indirectly assess disease association assumingthat the minor allele at SNP rs200 is truly disease-predisposing for athreshold level of power. If one sets the threshold level of power to be80%, then r_(T) ²=0.489 given the same significance level and chromosomenumbers as above. Hence, any SNP with a pairwise r² value with rs200greater than 0.489 is expected to have greater than 80% power to detectthe disease association. Further, this is assuming the conservativemodel where the LD SNP is disease-associated only through linkagedisequilibrium with the interrogated SNP rs200.

The contribution or association of particular SNPs and/or SNP haplotypeswith disease phenotypes, such as CVD, enables the SNPs of the presentinvention to be used to develop superior diagnostic tests capable ofidentifying individuals who express a detectable trait, such as CVD, asthe result of a specific genotype, or individuals whose genotype placesthem at an increased or decreased risk of developing a detectable traitat a subsequent time as compared to individuals who do not have thatgenotype. As described herein, diagnostics may be based on a single SNPor a group of SNPs. Combined detection of a plurality of SNPs (forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between,or more, of the SNPs provided in Table 1 and/or Table 2) typicallyincreases the probability of an accurate diagnosis. For example, thepresence of a single SNP known to correlate with CVD might indicate aprobability of 20% that an individual has or is at risk of developingCVD, whereas detection of five SNPs, each of which correlates with CVD,might indicate a probability of 80% that an individual has or is at riskof developing CVD. To further increase the accuracy of diagnosis orpredisposition screening, analysis of the SNPs of the present inventioncan be combined with that of other polymorphisms or other risk factorsof CVD, such as disease symptoms, pathological characteristics, familyhistory, diet, environmental factors or lifestyle factors.

It will be understood by practitioners skilled in the treatment ordiagnosis of CVD that the present invention generally does not intend toprovide an absolute identification of individuals who are at risk (orless at risk) of developing CVD, and/or pathologies related to CVD, butrather to indicate a certain increased (or decreased) degree orlikelihood of developing the disease based on statistically significantassociation results. However, this information is extremely valuable asit can be used to, for example, initiate preventive treatments or toallow an individual carrying one or more significant SNPs or SNPhaplotypes to foresee warning signs such as minor clinical symptoms, orto have regularly scheduled physical exams to monitor for appearance ofa condition in order to identify and begin treatment of the condition atan early stage. Particularly with diseases that are extremelydebilitating or fatal if not treated on time, the knowledge of apotential predisposition, even if this predisposition is not absolute,would likely contribute in a very significant manner to treatmentefficacy.

The diagnostic techniques of the present invention may employ a varietyof methodologies to determine whether a test subject has a SNP or a SNPpattern associated with an increased or decreased risk of developing adetectable trait or whether the individual suffers from a detectabletrait as a result of a particular polymorphism/mutation, including, forexample, methods which enable the analysis of individual chromosomes forhaplotyping, family studies, single sperm DNA analysis, or somatichybrids. The trait analyzed using the diagnostics of the invention maybe any detectable trait that is commonly observed in pathologies anddisorders related to CVD.

Another aspect of the present invention relates to a method ofdetermining whether an individual is at risk (or less at risk) ofdeveloping one or more traits or whether an individual expresses one ormore traits as a consequence of possessing a particular trait-causing ortrait-influencing allele. These methods generally involve obtaining anucleic acid sample from an individual and assaying the nucleic acidsample to determine which nucleotide(s) is/are present at one or moreSNP positions, wherein the assayed nucleotide(s) is/are indicative of anincreased or decreased risk of developing the trait or indicative thatthe individual expresses the trait as a result of possessing aparticular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the presentinvention are used to determine whether an individual has one or moreSNP allele(s) affecting the level (e.g., the concentration of mRNA orprotein in a sample, etc.) or pattern (e.g., the kinetics of expression,rate of decomposition, stability profile, Km, Vmax, etc.) of geneexpression (collectively, the “gene response” of a cell or bodilyfluid). Such a determination can be accomplished by screening for mRNAor protein expression (e.g., by using nucleic acid arrays, RT-PCR,TaqMan assays, or mass spectrometry), identifying genes having alteredexpression in an individual, genotyping SNPs disclosed in Table 1 and/orTable 2 that could affect the expression of the genes having alteredexpression (e.g., SNPs that are in and/or around the gene(s) havingaltered expression, SNPs in regulatory/control regions, SNPs in and/oraround other genes that are involved in pathways that could affect theexpression of the gene(s) having altered expression, or all SNPs couldbe genotyped), and correlating SNP genotypes with altered geneexpression. In this manner, specific SNP alleles at particular SNP sitescan be identified that affect gene expression.

Therapeutics, Pharmacogenomics, and Drug Development

Therapeutic Methods and Compositions

In certain aspects of the invention, there are provided methods ofassaying (i.e., testing) one or more SNPs provided by the presentinvention in an individual's nucleic acids, and administering atherapeutic or preventive agent to the individual based on the allele(s)present at the SNP(s) having indicated that the individual can benefitfrom the therapeutic or preventive agent.

In further aspects of the invention, there are provided methods ofassaying one or more SNPs provided by the present invention in anindividual's nucleic acids, and administering a diagnostic agent (e.g.,an imaging agent), or otherwise carrying out further diagnosticprocedures on the individual, based on the allele(s) present at theSNP(s) having indicated that the diagnostic agents or diagnosticsprocedures are justified in the individual.

In yet other aspects of the invention, there is provided apharmaceutical pack comprising a therapeutic agent (e.g., a smallmolecule drug, antibody, peptide, antisense or RNAi nucleic acidmolecule, etc.) and a set of instructions for administration of thetherapeutic agent to an individual who has been tested for one or moreSNPs provided by the present invention.

Pharmacogenomics

The present invention provides methods for assessing thepharmacogenomics of a subject harboring particular SNP alleles orhaplotypes to a particular therapeutic agent or pharmaceutical compound,or to a class of such compounds. Pharmacogenomics deals with the roleswhich clinically significant hereditary variations (e.g., SNPs) play inthe response to drugs due to altered drug disposition and/or abnormalaction in affected persons. See, e.g., Roses, Nature 405, 857-865(2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001);Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); andLinder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of thesevariations can result in severe toxicity of therapeutic drugs in certainindividuals or therapeutic failure of drugs in certain individuals as aresult of individual variation in metabolism. Thus, the SNP genotype ofan individual can determine the way a therapeutic compound acts on thebody or the way the body metabolizes the compound. For example, SNPs indrug metabolizing enzymes can affect the activity of these enzymes,which in turn can affect both the intensity and duration of drug action,as well as drug metabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters,proteins for pharmaceutical agents, and other drug targets has explainedwhy some patients do not obtain the expected drug effects, show anexaggerated drug effect, or experience serious toxicity from standarddrug dosages. SNPs can be expressed in the phenotype of the extensivemetabolizer and in the phenotype of the poor metabolizer. Accordingly,SNPs may lead to allelic variants of a protein in which one or more ofthe protein functions in one population are different from those inanother population. SNPs and the encoded variant peptides thus providetargets to ascertain a genetic predisposition that can affect treatmentmodality. For example, in a ligand-based treatment, SNPs may give riseto amino terminal extracellular domains and/or other ligand-bindingregions of a receptor that are more or less active in ligand binding,thereby affecting subsequent protein activation. Accordingly, liganddosage would necessarily be modified to maximize the therapeutic effectwithin a given population containing particular SNP alleles orhaplotypes.

As an alternative to genotyping, specific variant proteins containingvariant amino acid sequences encoded by alternative SNP alleles could beidentified. Thus, pharmacogenomic characterization of an individualpermits the selection of effective compounds and effective dosages ofsuch compounds for prophylactic or therapeutic uses based on theindividual's SNP genotype, thereby enhancing and optimizing theeffectiveness of the therapy. Furthermore, the production of recombinantcells and transgenic animals containing particular SNPs/haplotypes alloweffective clinical design and testing of treatment compounds and dosageregimens. For example, transgenic animals can be produced that differonly in specific SNP alleles in a gene that is orthologous to a humandisease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provideseveral significant advantages for patient care, particularly inpredicting an individual's predisposition to CVD (e.g., CHD, such as MI,or hypertension) and in predicting an individual's responsiveness to adrug (particularly for treating or preventing CVD). Pharmacogenomiccharacterization of an individual, based on an individual's SNPgenotype, can identify those individuals unlikely to respond totreatment with a particular medication and thereby allows physicians toavoid prescribing the ineffective medication to those individuals. Onthe other hand, SNP genotyping of an individual may enable physicians toselect the appropriate medication and dosage regimen that will be mosteffective based on an individual's SNP genotype. This informationincreases a physician's confidence in prescribing medications andmotivates patients to comply with their drug regimens. Furthermore,pharmacogenomics may identify patients predisposed to toxicity andadverse reactions to particular drugs or drug dosages. Adverse drugreactions lead to more than 100,000 avoidable deaths per year in theUnited States alone and therefore represent a significant cause ofhospitalization and death, as well as a significant economic burden onthe healthcare system (Pfost et al., Trends in Biotechnology, August2000.). Thus, pharmacogenomics based on the SNPs disclosed herein hasthe potential to both save lives and reduce healthcare costssubstantially.

Pharmacogenomics in general is discussed further in Rose et al.,“Pharmacogenetic analysis of clinically relevant genetic polymorphisms,”Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates toAlzheimer's disease and other neurodegenerative disorders is discussedin Cacabelos, “Pharmacogenomics for the treatment of dementia,” Ann Med34(5):357-79 (2002); Maimone et al., “Pharmacogenomics ofneurodegenerative diseases,” Eur J Pharmacol 413(1):11-29 (February2001); and Poirier, “Apolipoprotein E: a pharmacogenetic target for thetreatment of Alzheimer's disease,” Mol Diagn 4(4):335-41 (Dec. 1999).Pharmacogenomics as it relates to cardiovascular disorders is discussedin Siest et al., “Pharmacogenomics of drugs affecting the cardiovascularsystem,” Clin Chem Lab Med 41(4):590-9 (April 2003); Mukherjee et al.,“Pharmacogenomics in cardiovascular diseases,” Prog Cardiovasc Dis44(6):479-98 (May-June 2002); and Mooser et al., “Cardiovascularpharmacogenetics in the SNP era,” J Thromb Haemost 1(7):1398-402 (July2003). Pharmacogenomics as it relates to cancer is discussed in McLeodet al., “Cancer pharmacogenomics: SNPs, chips, and the individualpatient,” Cancer Invest 21(4):630-40 (2003); and Watters et al., “Cancerpharmacogenomics: current and future applications,” Biochim Biophys Acta1603(2):99-111 (March 2003).

Clinical Trials

In certain aspects of the invention, there are provided methods of usingthe SNPs disclosed herein to identify or stratify patient populationsfor clinical trials of a therapeutic, preventive, or diagnostic agent.

For instance, an aspect of the present invention includes selectingindividuals for clinical trials based on their SNP genotype, such asselecting individuals for inclusion in a clinical trial and/or assigningindividuals to a particular group within a clinical trial (e.g., an“arm” or “cohort” of the trial). For example, individuals with SNPgenotypes that indicate that they are likely to positively respond to adrug can be included in the trials, whereas those individuals whose SNPgenotypes indicate that they are less likely to or would not respond tothe drug, or who are at risk for suffering toxic effects or otheradverse reactions, can be excluded from the clinical trials. This notonly can improve the safety of clinical trials, but also can enhance thechances that the trial will demonstrate statistically significantefficacy.

Thus, certain embodiments of the invention provide methods forconducting a clinical trial of a therapeutic agent in which a human isselected for inclusion in the clinical trial and/or assigned to aparticular group within a clinical trial based on the presence orabsence of one or more SNPs disclosed herein. In certain embodiments,the therapeutic agent is a statin.

In certain exemplary embodiments, SNPs of the invention can be used toselect individuals who are unlikely to respond positively to aparticular therapeutic agent (or class of therapeutic agents) based ontheir SNP genotype(s) to participate in a clinical trial of another typeof drug that may benefit them. Thus, in certain embodiments, the SNPs ofthe invention can be used to identify patient populations who do notadequately respond to current treatments and are therefore in need ofnew therapies. This not only benefits the patients themselves, but alsobenefits organizations such as pharmaceutical companies by enabling theidentification of populations that represent markets for new drugs, andenables the efficacy of these new drugs to be tested during clinicaltrials directly in individuals within these markets.

The SNP-containing nucleic acid molecules of the present invention arealso useful for monitoring the effectiveness of modulating compounds onthe expression or activity of a variant gene, or encoded product,particularly in a treatment regimen or in clinical trials. Thus, thegene expression pattern can serve as an indicator for the continuingeffectiveness of treatment with the compound, particularly withcompounds to which a patient can develop resistance, as well as anindicator for toxicities. The gene expression pattern can also serve asa marker indicative of a physiological response of the affected cells tothe compound. Accordingly, such monitoring would allow either increasedadministration of the compound or the administration of alternativecompounds to which the patient has not become resistant.

Furthermore, the SNPs of the present invention may have utility indetermining why certain previously developed drugs performed poorly inclinical trials and may help identify a subset of the population thatwould benefit from a drug that had previously performed poorly inclinical trials, thereby “rescuing” previously developed drugs, andenabling the drug to be made available to a particular CVD patientpopulation that can benefit from it.

Identification, Screening, and Use of Therapeutic Agents

The SNPs of the present invention also can be used to identify noveltherapeutic targets for CVD. For example, genes containing thedisease-associated variants (“variant genes”) or their products, as wellas genes or their products that are directly or indirectly regulated byor interacting with these variant genes or their products, can betargeted for the development of therapeutics that, for example, treatthe disease or prevent or delay disease onset. The therapeutics may becomposed of, for example, small molecules, proteins, protein fragmentsor peptides, antibodies, nucleic acids, or their derivatives or mimeticswhich modulate the functions or levels of the target genes or geneproducts.

The invention further provides methods for identifying a compound oragent that can be used to treat CVD. The SNPs disclosed herein areuseful as targets for the identification and/or development oftherapeutic agents. A method for identifying a therapeutic agent orcompound typically includes assaying the ability of the agent orcompound to modulate the activity and/or expression of a SNP-containingnucleic acid or the encoded product and thus identifying an agent or acompound that can be used to treat a disorder characterized by undesiredactivity or expression of the SNP-containing nucleic acid or the encodedproduct. The assays can be performed in cell-based and cell-freesystems. Cell-based assays can include cells naturally expressing thenucleic acid molecules of interest or recombinant cells geneticallyengineered to express certain nucleic acid molecules.

Variant gene expression in a CVD patient can include, for example,either expression of a SNP-containing nucleic acid sequence (forinstance, a gene that contains a SNP can be transcribed into an mRNAtranscript molecule containing the SNP, which can in turn be translatedinto a variant protein) or altered expression of a normal/wild-typenucleic acid sequence due to one or more SNPs (for instance, aregulatory/control region can contain a SNP that affects the level orpattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleicacid levels (e.g., mRNA levels), expressed protein levels, or ofcollateral compounds involved in a signal pathway. Further, theexpression of genes that are up- or down-regulated in response to thesignal pathway can also be assayed. In this embodiment, the regulatoryregions of these genes can be operably linked to a reporter gene such asluciferase.

Modulators of variant gene expression can be identified in a methodwherein, for example, a cell is contacted with a candidatecompound/agent and the expression of mRNA determined. The level ofexpression of mRNA in the presence of the candidate compound is comparedto the level of expression of mRNA in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof variant gene expression based on this comparison and be used to treata disorder such as CVD that is characterized by variant gene expression(e.g., either expression of a SNP-containing nucleic acid or alteredexpression of a normal/wild-type nucleic acid molecule due to one ormore SNPs that affect expression of the nucleic acid molecule) due toone or more SNPs of the present invention. When expression of mRNA isstatistically significantly greater in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of nucleic acid expression. When nucleic acid expression isstatistically significantly less in the presence of the candidatecompound than in its absence, the candidate compound is identified as aninhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP orassociated nucleic acid domain (e.g., catalytic domain,ligand/substrate-binding domain, regulatory/control region, etc.) orgene, or the encoded mRNA transcript, as a target, using a compoundidentified through drug screening as a gene modulator to modulatevariant nucleic acid expression. Modulation can include eitherup-regulation (i.e., activation or agonization) or down-regulation(i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type orvariant, may be altered in individuals with a particular SNP allele in aregulatory/control element, such as a promoter or transcription factorbinding domain, that regulates expression. In this situation, methods oftreatment and compounds can be identified, as discussed herein, thatregulate or overcome the variant regulatory/control element, therebygenerating normal, or healthy, expression levels of either the wild typeor variant protein.

Pharmaceutical Compositions and Administration Thereof

Any of the CVD-associated proteins, and encoding nucleic acid molecules,disclosed herein can be used as therapeutic targets (or directly usedthemselves as therapeutic compounds) for treating or preventing CVD orrelated pathologies, and the present disclosure enables therapeuticcompounds (e.g., small molecules, antibodies, therapeutic proteins, RNAiand antisense molecules, etc.) to be developed that target (or arecomprised of) any of these therapeutic targets.

In general, a therapeutic compound will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the therapeutic compound of this invention, i.e., the activeingredient, will depend upon numerous factors such as the severity ofthe disease to be treated, the age and relative health of the subject,the potency of the compound used, the route and form of administration,and other factors.

Therapeutically effective amounts of therapeutic compounds may rangefrom, for example, approximately 0.01-50 mg per kilogram body weight ofthe recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as anexample, for administration to a 70-kg person, the dosage range wouldmost preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceuticalcompositions by any one of the following routes: oral, systemic (e.g.,transdermal, intranasal, or by suppository), or parenteral (e.g.,intramuscular, intravenous, or subcutaneous) administration. Thepreferred manner of administration is oral or parenteral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Oral compositions can take the form of tablets,pills, capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills, or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeuticcompound in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the therapeuticcompound. Such excipients may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences 18^(th) ed., E. W.Martin, ed., Mack Publishing Company (1990).

The amount of the therapeutic compound in a formulation can vary withinthe full range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of the therapeutic compound based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about1-80% wt.

Therapeutic compounds can be administered alone or in combination withother therapeutic compounds or in combination with one or more otheractive ingredient(s). For example, an inhibitor or stimulator of aCVD-associated protein can be administered in combination with anotheragent that inhibits or stimulates the activity of the same or adifferent CVD-associated protein to thereby counteract the effects ofCVD.

For further information regarding pharmacology, see Current Protocols inPharmacology, John Wiley & Sons, Inc., N.Y.

Nucleic Acid-Based Therapeutic Agents

The SNP-containing nucleic acid molecules disclosed herein, and theircomplementary nucleic acid molecules, may be used as antisenseconstructs to control gene expression in cells, tissues, and organisms.Antisense technology is well established in the art and extensivelyreviewed in Antisense Drug Technology: Principles, Strategies, andApplications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). Anantisense nucleic acid molecule is generally designed to becomplementary to a region of mRNA expressed by a gene so that theantisense molecule hybridizes to the mRNA and thereby blocks translationof mRNA into protein. Various classes of antisense oligonucleotides areused in the art, two of which are cleavers and blockers. Cleavers, bybinding to target RNAs, activate intracellular nucleases (e.g., RNaseHor RNase L) that cleave the target RNA. Blockers, which also bind totarget RNAs, inhibit protein translation through steric hindrance ofribosomes. Exemplary blockers include peptide nucleic acids,morpholinos, locked nucleic acids, and methylphosphonates. See, e.g.,Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisenseoligonucleotides are directly useful as therapeutic agents, and are alsouseful for determining and validating gene function (e.g., in geneknock-out or knock-down experiments).

Antisense technology is further reviewed in: Layery et al., “Antisenseand RNAi: powerful tools in drug target discovery and validation,” CurrOpin Drug Discov Devel 6(4):561-9 (July 2003); Stephens et al.,“Antisense oligonucleotide therapy in cancer,” Curr Opin Mol Ther5(2):118-22 (April 2003); Kurreck, “Antisense technologies. Improvementthrough novel chemical modifications,” Eur J Biochem 270(8):1628-44(April 2003); Dias et al., “Antisense oligonucleotides: basic conceptsand mechanisms,” Mol Cancer Ther 1(5):347-55 (March 2002); Chen,“Clinical development of antisense oligonucleotides as anti-cancertherapeutics,” Methods Mol Med 75:621-36 (2003); Wang et al., “Antisenseanticancer oligonucleotide therapeutics,” Curr Cancer Drug Targets1(3):177-96 (November 2001); and Bennett, “Efficiency of antisenseoligonucleotide drug discovery,” Antisense Nucleic Acid Drug Dev12(3):215-24 (June 2002).

The SNPs of the present invention are particularly useful for designingantisense reagents that are specific for particular nucleic acidvariants. Based on the SNP information disclosed herein, antisenseoligonucleotides can be produced that specifically target mRNA moleculesthat contain one or more particular SNP nucleotides. In this manner,expression of mRNA molecules that contain one or more undesiredpolymorphisms (e.g., SNP nucleotides that lead to a defective proteinsuch as an amino acid substitution in a catalytic domain) can beinhibited or completely blocked. Thus, antisense oligonucleotides can beused to specifically bind a particular polymorphic form (e.g., a SNPallele that encodes a defective protein), thereby inhibiting translationof this form, but which do not bind an alternative polymorphic form(e.g., an alternative SNP nucleotide that encodes a protein havingnormal function).

Antisense molecules can be used to inactivate mRNA in order to inhibitgene expression and production of defective proteins. Accordingly, thesemolecules can be used to treat a disorder, such as CVD, characterized byabnormal or undesired gene expression or expression of certain defectiveproteins. This technique can involve cleavage by means of ribozymescontaining nucleotide sequences complementary to one or more regions inthe mRNA that attenuate the ability of the mRNA to be translated.Possible mRNA regions include, for example, protein-coding regions andparticularly protein-coding regions corresponding to catalyticactivities, substrate/ligand binding, or other functional activities ofa protein.

The SNPs of the present invention are also useful for designing RNAinterference reagents that specifically target nucleic acid moleculeshaving particular SNP variants. RNA interference (RNAi), also referredto as gene silencing, is based on using double-stranded RNA (dsRNA)molecules to turn genes off. When introduced into a cell, dsRNAs areprocessed by the cell into short fragments (generally about 21, 22, or23 nucleotides in length) known as small interfering RNAs (siRNAs) whichthe cell uses in a sequence-specific manner to recognize and destroycomplementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917(2002). Accordingly, an aspect of the present invention specificallycontemplates isolated nucleic acid molecules that are about 18-26nucleotides in length, preferably 19-25 nucleotides in length, and morepreferably 20, 21, 22, or 23 nucleotides in length, and the use of thesenucleic acid molecules for RNAi. Because RNAi molecules, includingsiRNAs, act in a sequence-specific manner, the SNPs of the presentinvention can be used to design RNAi reagents that recognize and destroynucleic acid molecules having specific SNP alleles/nucleotides (such asdeleterious alleles that lead to the production of defective proteins),while not affecting nucleic acid molecules having alternative SNPalleles (such as alleles that encode proteins having normal function).As with antisense reagents, RNAi reagents may be directly useful astherapeutic agents (e.g., for turning off defective, disease-causinggenes), and are also useful for characterizing and validating genefunction (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds etal., “Rational siRNA design for RNA interference,” Nat Biotechnol22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et al., “Genomewideview of gene silencing by small interfering RNAs,” PNAS100(11):6343-6346 (2003); Vickers et al., “Efficient Reduction of TargetRNAs by Small Interfering RNA and RNase H-dependent Antisense Agents,” JBiol Chem 278:7108-7118 (2003); Agami, “RNAi and related mechanisms andtheir potential use for therapy,” Curr Opin Chem Biol 6(6):829-34 (Dec.2002); Layery et al., “Antisense and RNAi: powerful tools in drug targetdiscovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July2003); Shi, “Mammalian RNAi for the masses,” Trends Genet. 19(1):9-12(January 2003); Shuey et al., “RNAi: gene-silencing in therapeuticintervention,” Drug Discovery Today 7(20):1040-1046 (October 2002);McManus et al., Nat Rev Genet 3(10):737-47 (October 2002); Xia et al.,Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al., Curr OpinGenet Dev 10(5):562-7 (October 2000); Bosher et al., Nat Cell Biol2(2):E31-6 (February 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (June1999).

Other Therapeutic Aspects

SNPs have many important uses in drug discovery, screening, anddevelopment, and thus the SNPs of the present invention are useful forimproving many different aspects of the drug development process.

For example, a high probability exists that, for any gene/proteinselected as a potential drug target, variants of that gene/protein willexist in a patient population. Thus, determining the impact ofgene/protein variants on the selection and delivery of a therapeuticagent should be an integral aspect of the drug discovery and developmentprocess. Jazwinska, A Trends Guide to Genetic Variation and GenomicMedicine S30-S36 (March 2002).

Knowledge of variants (e.g., SNPs and any corresponding amino acidpolymorphisms) of a particular therapeutic target (e.g., a gene, mRNAtranscript, or protein) enables parallel screening of the variants inorder to identify therapeutic candidates (e.g., small moleculecompounds, antibodies, antisense or RNAi nucleic acid compounds, etc.)that demonstrate efficacy across variants. Rothberg, Nat Biotechnol19(3):209-11 (March 2001). Such therapeutic candidates would be expectedto show equal efficacy across a larger segment of the patientpopulation, thereby leading to a larger potential market for thetherapeutic candidate.

Furthermore, identifying variants of a potential therapeutic targetenables the most common form of the target to be used for selection oftherapeutic candidates, thereby helping to ensure that the experimentalactivity that is observed for the selected candidates reflects the realactivity expected in the largest proportion of a patient population.Jazwinska, A Trends Guide to Genetic Variation and Genomic MedicineS30-S36 (March 2002).

Additionally, screening therapeutic candidates against all knownvariants of a target can enable the early identification of potentialtoxicities and adverse reactions relating to particular variants. Forexample, variability in drug absorption, distribution, metabolism andexcretion (ADME) caused by, for example, SNPs in therapeutic targets ordrug metabolizing genes, can be identified, and this information can beutilized during the drug development process to minimize variability indrug disposition and develop therapeutic agents that are safer across awider range of a patient population. The SNPs of the present invention,including the variant proteins and encoding polymorphic nucleic acidmolecules provided in Tables 1 and 2, are useful in conjunction with avariety of toxicology methods established in the art, such as those setforth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (ornucleic acid molecules, either RNA or DNA) may cross-react with thevariant proteins (or polymorphic nucleic acid molecules) disclosed inTable 1, thereby significantly affecting the pharmacokinetic propertiesof the drug. Consequently, the protein variants and the SNP-containingnucleic acid molecules disclosed in Tables 1 and 2 are useful indeveloping, screening, and evaluating therapeutic agents that targetcorresponding art-known protein forms (or nucleic acid molecules).Additionally, as discussed above, knowledge of all polymorphic forms ofa particular drug target enables the design of therapeutic agents thatare effective against most or all such polymorphic forms of the drugtarget.

A subject suffering from a pathological condition ascribed to a SNP,such as CVD, may be treated so as to correct the genetic defect. SeeKren et al., Proc Natl Acad Sci USA 96:10349-10354 (1999). Such asubject can be identified by any method that can detect the polymorphismin a biological sample drawn from the subject. Such a genetic defect maybe permanently corrected by administering to such a subject a nucleicacid fragment incorporating a repair sequence that supplies thenormal/wild-type nucleotide at the position of the SNP. Thissite-specific repair sequence can encompass an RNA/DNA oligonucleotidethat operates to promote endogenous repair of a subject's genomic DNA.The site-specific repair sequence is administered in an appropriatevehicle, such as a complex with polyethylenimine, encapsulated inanionic liposomes, a viral vector such as an adenovirus, or otherpharmaceutical composition that promotes intracellular uptake of theadministered nucleic acid. A genetic defect leading to an inbornpathology may then be overcome, as the chimeric oligonucleotides induceincorporation of the normal sequence into the subject's genome. Uponincorporation, the normal gene product is expressed, and the replacementis propagated, thereby engendering a permanent repair and therapeuticenhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribedto be the cause of, or a contributing factor to, a pathologicalcondition, a method of treating such a condition can includeadministering to a subject experiencing the pathology thewild-type/normal cognate of the variant protein. Once administered in aneffective dosing regimen, the wild-type cognate provides complementationor remediation of the pathological condition.

Human Identification Applications

In addition to their diagnostic, therapeutic, and preventive uses in CVDand related pathologies, the SNPs provided by the present invention arealso useful as human identification markers for such applications asforensics, paternity testing, and biometrics. See, e.g., Gill, “Anassessment of the utility of single nucleotide polymorphisms (SNPs) forforensic purposes,” Int J Legal Med 114(4-5):204-10 (2001). Geneticvariations in the nucleic acid sequences between individuals can be usedas genetic markers to identify individuals and to associate a biologicalsample with an individual. Determination of which nucleotides occupy aset of SNP positions in an individual identifies a set of SNP markersthat distinguishes the individual. The more SNP positions that areanalyzed, the lower the probability that the set of SNPs in oneindividual is the same as that in an unrelated individual. Preferably,if multiple sites are analyzed, the sites are unlinked (i.e., inheritedindependently). Thus, preferred sets of SNPs can be selected from amongthe SNPs disclosed herein, which may include SNPs on differentchromosomes, SNPs on different chromosome arms, and/or SNPs that aredispersed over substantial distances along the same chromosome arm.

Furthermore, among the SNPs disclosed herein, preferred SNPs for use incertain forensic/human identification applications include SNPs locatedat degenerate codon positions (i.e., the third position in certaincodons which can be one of two or more alternative nucleotides and stillencode the same amino acid), since these SNPs do not affect the encodedprotein. SNPs that do not affect the encoded protein are expected to beunder less selective pressure and are therefore expected to be morepolymorphic in a population, which is typically an advantage forforensic/human identification applications. However, for certainforensics/human identification applications, such as predictingphenotypic characteristics (e.g., inferring ancestry or inferring one ormore physical characteristics of an individual) from a DNA sample, itmay be desirable to utilize SNPs that affect the encoded protein.

For many of the SNPs disclosed in Tables 1 and 2 (which are identifiedas “Applera” SNP source), Tables 1 and 2 provide SNP allele frequenciesobtained by re-sequencing the DNA of chromosomes from 39 individuals(Tables 1 and 2 also provide allele frequency information for “Celera”source SNPs and, where available, public SNPs from dbEST, HGBASE, and/orHGMD). The allele frequencies provided in Tables 1 and 2 enable theseSNPs to be readily used for human identification applications. Althoughany SNP disclosed in Table 1 and/or Table 2 could be used for humanidentification, the closer that the frequency of the minor allele at aparticular SNP site is to 50%, the greater the ability of that SNP todiscriminate between different individuals in a population since itbecomes increasingly likely that two randomly selected individuals wouldhave different alleles at that SNP site. Using the SNP allelefrequencies provided in Tables 1 and 2, one of ordinary skill in the artcould readily select a subset of SNPs for which the frequency of theminor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%,40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables1 and 2 provide allele frequencies based on the re-sequencing of thechromosomes from 39 individuals, a subset of SNPs could readily beselected for human identification in which the total allele count of theminor allele at a particular SNP site is, for example, at least 1, 2, 4,8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other numberin-between.

Furthermore, Tables 1 and 2 also provide population group(interchangeably referred to herein as ethnic or racial groups)information coupled with the extensive allele frequency information. Forexample, the group of 39 individuals whose DNA was re-sequenced wasmade-up of 20 Caucasians and 19 African-Americans. This population groupinformation enables further refinement of SNP selection for humanidentification. For example, preferred SNPs for human identification canbe selected from Tables 1 and 2 that have similar allele frequencies inboth the Caucasian and African-American populations; thus, for example,SNPs can be selected that have equally high discriminatory power in bothpopulations. Alternatively, SNPs can be selected for which there is astatistically significant difference in allele frequencies between theCaucasian and African-American populations (as an extreme example, aparticular allele may be observed only in either the Caucasian or theAfrican-American population group but not observed in the otherpopulation group); such SNPs are useful, for example, for predicting therace/ethnicity of an unknown perpetrator from a biological sample suchas a hair or blood stain recovered at a crime scene. For a discussion ofusing SNPs to predict ancestry from a DNA sample, including statisticalmethods, see Frudakis et al., “A Classifier for the SNP-Based Inferenceof Ancestry,” Journal of Forensic Sciences 48(4):771-782 (2003).

SNPs have numerous advantages over other types of polymorphic markers,such as short tandem repeats (STRs). For example, SNPs can be easilyscored and are amenable to automation, making SNPs the markers of choicefor large-scale forensic databases. SNPs are found in much greaterabundance throughout the genome than repeat polymorphisms. Populationfrequencies of two polymorphic forms can usually be determined withgreater accuracy than those of multiple polymorphic forms atmulti-allelic loci. SNPs are mutationally more stable than repeatpolymorphisms. SNPs are not susceptible to artifacts such as stutterbands that can hinder analysis. Stutter bands are frequently encounteredwhen analyzing repeat polymorphisms, and are particularly troublesomewhen analyzing samples such as crime scene samples that may containmixtures of DNA from multiple sources. Another significant advantage ofSNP markers over STR markers is the much shorter length of nucleic acidneeded to score a SNP. For example, STR markers are generally severalhundred base pairs in length. A SNP, on the other hand, comprises asingle nucleotide, and generally a short conserved region on either sideof the SNP position for primer and/or probe binding. This makes SNPsmore amenable to typing in highly degraded or aged biological samplesthat are frequently encountered in forensic casework in which DNA may befragmented into short pieces.

SNPs also are not subject to microvariant and “off-ladder” allelesfrequently encountered when analyzing STR loci. Microvariants aredeletions or insertions within a repeat unit that change the size of theamplified DNA product so that the amplified product does not migrate atthe same rate as reference alleles with normal sized repeat units. Whenseparated by size, such as by electrophoresis on a polyacrylamide gel,microvariants do not align with a reference allelic ladder of standardsized repeat units, but rather migrate between the reference alleles.The reference allelic ladder is used for precise sizing of alleles forallele classification; therefore alleles that do not align with thereference allelic ladder lead to substantial analysis problems.Furthermore, when analyzing multi-allelic repeat polymorphisms,occasionally an allele is found that consists of more or less repeatunits than has been previously seen in the population, or more or lessrepeat alleles than are included in a reference allelic ladder. Thesealleles will migrate outside the size range of known alleles in areference allelic ladder, and therefore are referred to as “off-ladder”alleles. In extreme cases, the allele may contain so few or so manyrepeats that it migrates well out of the range of the reference allelicladder. In this situation, the allele may not even be observed, or, withmultiplex analysis, it may migrate within or close to the size range foranother locus, further confounding analysis.

SNP analysis avoids the problems of microvariants and off-ladder allelesencountered in STR analysis. Importantly, microvariants and off-ladderalleles may provide significant problems, and may be completely missed,when using analysis methods such as oligonucleotide hybridizationarrays, which utilize oligonucleotide probes specific for certain knownalleles. Furthermore, off-ladder alleles and microvariants encounteredwith STR analysis, even when correctly typed, may lead to improperstatistical analysis, since their frequencies in the population aregenerally unknown or poorly characterized, and therefore the statisticalsignificance of a matching genotype may be questionable. All theseadvantages of SNP analysis are considerable in light of the consequencesof most DNA identification cases, which may lead to life imprisonmentfor an individual, or re-association of remains to the family of adeceased individual.

DNA can be isolated from biological samples such as blood, bone, hair,saliva, or semen, and compared with the DNA from a reference source atparticular SNP positions. Multiple SNP markers can be assayedsimultaneously in order to increase the power of discrimination and thestatistical significance of a matching genotype. For example,oligonucleotide arrays can be used to genotype a large number of SNPssimultaneously. The SNPs provided by the present invention can beassayed in combination with other polymorphic genetic markers, such asother SNPs known in the art or STRs, in order to identify an individualor to associate an individual with a particular biological sample.

Furthermore, the SNPs provided by the present invention can be genotypedfor inclusion in a database of DNA genotypes, for example, a criminalDNA databank such as the FBI's Combined DNA Index System (CODIS)database. A genotype obtained from a biological sample of unknown sourcecan then be queried against the database to find a matching genotype,with the SNPs of the present invention providing nucleotide positions atwhich to compare the known and unknown DNA sequences for identity.Accordingly, the present invention provides a database comprising novelSNPs or SNP alleles of the present invention (e.g., the database cancomprise information indicating which alleles are possessed byindividual members of a population at one or more novel SNP sites of thepresent invention), such as for use in forensics, biometrics, or otherhuman identification applications. Such a database typically comprises acomputer-based system in which the SNPs or SNP alleles of the presentinvention are recorded on a computer readable medium.

The SNPs of the present invention can also be assayed for use inpaternity testing. The object of paternity testing is usually todetermine whether a male is the father of a child. In most cases, themother of the child is known and thus, the mother's contribution to thechild's genotype can be traced. Paternity testing investigates whetherthe part of the child's genotype not attributable to the mother isconsistent with that of the putative father. Paternity testing can beperformed by analyzing sets of polymorphisms in the putative father andthe child, with the SNPs of the present invention providing nucleotidepositions at which to compare the putative father's and child's DNAsequences for identity. If the set of polymorphisms in the childattributable to the father does not match the set of polymorphisms ofthe putative father, it can be concluded, barring experimental error,that the putative father is not the father of the child. If the set ofpolymorphisms in the child attributable to the father match the set ofpolymorphisms of the putative father, a statistical calculation can beperformed to determine the probability of coincidental match, and aconclusion drawn as to the likelihood that the putative father is thetrue biological father of the child.

In addition to paternity testing, SNPs are also useful for other typesof kinship testing, such as for verifying familial relationships forimmigration purposes, or for cases in which an individual alleges to berelated to a deceased individual in order to claim an inheritance fromthe deceased individual, etc. For further information regarding theutility of SNPs for paternity testing and other types of kinshiptesting, including methods for statistical analysis, see Krawczak,“Informativity assessment for biallelic single nucleotidepolymorphisms,” Electrophoresis 20(8):1676-81 (June 1999).

The use of the SNPs of the present invention for human identificationfurther extends to various authentication systems, commonly referred toas biometric systems, which typically convert physical characteristicsof humans (or other organisms) into digital data. Biometric systemsinclude various technological devices that measure such uniqueanatomical or physiological characteristics as finger, thumb, or palmprints; hand geometry; vein patterning on the back of the hand; bloodvessel patterning of the retina and color and texture of the iris;facial characteristics; voice patterns; signature and typing dynamics;and DNA. Such physiological measurements can be used to verify identityand, for example, restrict or allow access based on the identification.Examples of applications for biometrics include physical area security,computer and network security, aircraft passenger check-in and boarding,financial transactions, medical records access, government benefitdistribution, voting, law enforcement, passports, visas and immigration,prisons, various military applications, and for restricting access toexpensive or dangerous items, such as automobiles or guns. See, forexample, O'Connor, Stanford Technology Law Review, and U.S. Pat. No.6,119,096.

Groups of SNPs, particularly the SNPs provided by the present invention,can be typed to uniquely identify an individual for biometricapplications such as those described above. Such SNP typing can readilybe accomplished using, for example, DNA chips/arrays. Preferably, aminimally invasive means for obtaining a DNA sample is utilized. Forexample, PCR amplification enables sufficient quantities of DNA foranalysis to be obtained from buccal swabs or fingerprints, which containDNA-containing skin cells and oils that are naturally transferred duringcontact.

Further information regarding techniques for using SNPs inforensic/human identification applications can be found, for example, inCurrent Protocols in Human Genetics 14.1-14.7, John Wiley & Sons, N.Y.(2002).

Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules,many of which encode proteins having variant amino acid sequences ascompared to the art-known (i.e., wild-type) proteins. Amino acidsequences encoded by the polymorphic nucleic acid molecules of thepresent invention are referred to as SEQ ID NOS:308-614 in Table 1 andprovided in the Sequence Listing. These variants will generally bereferred to herein as variant proteins/peptides/polypeptides, orpolymorphic proteins/peptides/polypeptides of the present invention. Theterms “protein,” “peptide,” and “polypeptide” are used hereininterchangeably.

A variant protein of the present invention may be encoded by, forexample, a nonsynonymous nucleotide substitution at any one of the cSNPpositions disclosed herein. In addition, variant proteins may alsoinclude proteins whose expression, structure, and/or function is alteredby a SNP disclosed herein, such as a SNP that creates or destroys a stopcodon, a SNP that affects splicing, and a SNP in control/regulatoryelements, e.g. promoters, enhancers, or transcription factor bindingdomains.

As used herein, a protein or peptide is said to be “isolated” or“purified” when it is substantially free of cellular material orchemical precursors or other chemicals. The variant proteins of thepresent invention can be purified to homogeneity or other lower degreesof purity. The level of purification will be based on the intended use.The key feature is that the preparation allows for the desired functionof the variant protein, even if in the presence of considerable amountsof other components.

As used herein, “substantially free of cellular material” includespreparations of the variant protein having less than about 30% (by dryweight) other proteins (i.e., contaminating protein), less than about20% other proteins, less than about 10% other proteins, or less thanabout 5% other proteins. When the variant protein is recombinantlyproduced, it can also be substantially free of culture medium, i.e.,culture medium represents less than about 20% of the volume of theprotein preparation.

The language “substantially free of chemical precursors or otherchemicals” includes preparations of the variant protein in which it isseparated from chemical precursors or other chemicals that are involvedin its synthesis. In one embodiment, the language “substantially free ofchemical precursors or other chemicals” includes preparations of thevariant protein having less than about 30% (by dry weight) chemicalprecursors or other chemicals, less than about 20% chemical precursorsor other chemicals, less than about 10% chemical precursors or otherchemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturallyexpress it, purified from cells that have been altered to express it(recombinant host cells), or synthesized using known protein synthesismethods. For example, a nucleic acid molecule containing SNP(s) encodingthe variant protein can be cloned into an expression vector, theexpression vector introduced into a host cell, and the variant proteinexpressed in the host cell. The variant protein can then be isolatedfrom the cells by any appropriate purification scheme using standardprotein purification techniques. Examples of these techniques aredescribed in detail below. Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The present invention provides isolated variant proteins that comprise,consist of or consist essentially of amino acid sequences that containone or more variant amino acids encoded by one or more codons thatcontain a SNP of the present invention.

Accordingly, the present invention provides variant proteins thatconsist of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists of an amino acid sequencewhen the amino acid sequence is the entire amino acid sequence of theprotein.

The present invention further provides variant proteins that consistessentially of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists essentially of an aminoacid sequence when such an amino acid sequence is present with only afew additional amino acid residues in the final protein.

The present invention further provides variant proteins that compriseamino acid sequences that contain one or more amino acid polymorphisms(or truncations or extensions due to creation or destruction of a stopcodon, respectively) encoded by the SNPs provided in Table 1 and/orTable 2. A protein comprises an amino acid sequence when the amino acidsequence is at least part of the final amino acid sequence of theprotein. In such a fashion, the protein may contain only the variantamino acid sequence or have additional amino acid residues, such as acontiguous encoded sequence that is naturally associated with it orheterologous amino acid residues. Such a protein can have a fewadditional amino acid residues or can comprise many more additionalamino acids. A brief description of how various types of these proteinscan be made and isolated is provided below.

The variant proteins of the present invention can be attached toheterologous sequences to form chimeric or fusion proteins. Suchchimeric and fusion proteins comprise a variant protein operativelylinked to a heterologous protein having an amino acid sequence notsubstantially homologous to the variant protein. “Operatively linked”indicates that the coding sequences for the variant protein and theheterologous protein are ligated in-frame. The heterologous protein canbe fused to the N-terminus or C-terminus of the variant protein. Inanother embodiment, the fusion protein is encoded by a fusionpolynucleotide that is synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers which give rise tocomplementary overhangs between two consecutive gene fragments which cansubsequently be annealed and re-amplified to generate a chimeric genesequence. See Ausubel et al., Current Protocols in Molecular Biology(1992). Moreover, many expression vectors are commercially availablethat already encode a fusion moiety (e.g., a GST protein). A variantprotein-encoding nucleic acid can be cloned into such an expressionvector such that the fusion moiety is linked in-frame to the variantprotein.

In many uses, the fusion protein does not affect the activity of thevariant protein. The fusion protein can include, but is not limited to,enzymatic fusion proteins, for example, beta-galactosidase fusions,yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-taggedand Ig fusions. Such fusion proteins, particularly poly-His fusions, canfacilitate their purification following recombinant expression. Incertain host cells (e.g., mammalian host cells), expression and/orsecretion of a protein can be increased by using a heterologous signalsequence. Fusion proteins are further described in, for example, Terpe,“Overview of tag protein fusions: from molecular and biochemicalfundamentals to commercial systems,” Appl Microbiol Biotechnol60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al.,“Designing proteins that work using recombinant technologies,” CurrPharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al.,“Affinity fusion strategies for detection, purification, andimmobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16(October 1997).

In certain embodiments, novel compositions of the present invention alsorelate to further obvious variants of the variant polypeptides of thepresent invention, such as naturally-occurring mature forms (e.g.,allelic variants), non-naturally occurring recombinantly-derivedvariants, and orthologs and paralogs of such proteins that sharesequence homology. Such variants can readily be generated usingart-known techniques in the fields of recombinant nucleic acidtechnology and protein biochemistry.

Further variants of the variant polypeptides disclosed in Table 1 cancomprise an amino acid sequence that shares at least 70-80%, 80-85%,85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identitywith an amino acid sequence disclosed in Table 1 (or a fragment thereof)and that includes a novel amino acid residue (allele) disclosed in Table1 (which is encoded by a novel SNP allele). Thus, an aspect of thepresent invention that is specifically contemplated are polypeptidesthat have a certain degree of sequence variation compared with thepolypeptide sequences shown in Table 1, but that contain a novel aminoacid residue (allele) encoded by a novel SNP allele disclosed herein. Inother words, as long as a polypeptide contains a novel amino acidresidue disclosed herein, other portions of the polypeptide that flankthe novel amino acid residue can vary to some degree from thepolypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, ofproteins that comprise one of the amino acid sequences disclosed hereincan readily be identified as having complete sequence identity to one ofthe variant proteins of the present invention as well as being encodedby the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having somedegree of significant sequence homology/identity to at least a portionof a variant peptide as well as being encoded by a gene from anotherorganism. Preferred orthologs will be isolated from non-human mammals,preferably primates, for the development of human therapeutic targetsand agents. Such orthologs can be encoded by a nucleic acid sequencethat hybridizes to a variant peptide-encoding nucleic acid moleculeunder moderate to stringent conditions depending on the degree ofrelatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containingdeletions, additions and substitutions in the amino acid sequence causedby the SNPs of the present invention. One class of substitutions isconserved amino acid substitutions in which a given amino acid in apolypeptide is substituted for another amino acid of likecharacteristics. Typical conservative substitutions are replacements,one for another, among the aliphatic amino acids Ala, Val, Leu, and IIe;interchange of the hydroxyl residues Ser and Thr; exchange of the acidicresidues Asp and Glu; substitution between the amide residues Asn andGln; exchange of the basic residues Lys and Arg; and replacements amongthe aromatic residues Phe and Tyr. Guidance concerning which amino acidchanges are likely to be phenotypically silent are found, for example,in Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one ormore activities, e.g. ability to bind another molecule, ability tocatalyze a substrate, ability to mediate signaling, etc. Fullyfunctional variants typically contain only conservative variations orvariations in non-critical residues or in non-critical regions.Functional variants can also contain substitution of similar amino acidsthat result in no change or an insignificant change in function.Alternatively, such substitutions may positively or negatively affectfunction to some degree. Non-functional variants typically contain oneor more non-conservative amino acid substitutions, deletions,insertions, inversions, truncations or extensions, or a substitution,insertion, inversion, or deletion of a critical residue or in a criticalregion.

Amino acids that are essential for function of a protein can beidentified by methods known in the art, such as site-directedmutagenesis or alanine-scanning mutagenesis, particularly using theamino acid sequence and polymorphism information provided in Table 1.Cunningham et al., Science 244:1081-1085 (1989). The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for biological activitysuch as enzyme activity or in assays such as an in vitro proliferativeactivity. Sites that are critical for binding partner/substrate bindingcan also be determined by structural analysis such as crystallization,nuclear magnetic resonance or photoaffinity labeling. Smith et al., JMol Biol 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).

Polypeptides can contain amino acids other than the 20 amino acidscommonly referred to as the 20 naturally occurring amino acids. Further,many amino acids, including the terminal amino acids, may be modified bynatural processes, such as processing and other post-translationalmodifications, or by chemical modification techniques well known in theart. Accordingly, the variant proteins of the present invention alsoencompass derivatives or analogs in which a substituted amino acidresidue is not one encoded by the genetic code, in which a substituentgroup is included, in which the mature polypeptide is fused with anothercompound, such as a compound to increase the half-life of thepolypeptide (e.g., polyethylene glycol), or in which additional aminoacids are fused to the mature polypeptide, such as a leader or secretorysequence or a sequence for purification of the mature polypeptide or apro-protein sequence.

Known protein modifications include, but are not limited to,acetylation, acylation, ADP-ribosylation, amidation, covalent attachmentof flavin, covalent attachment of a heme moiety, covalent attachment ofa nucleotide or nucleotide derivative, covalent attachment of a lipid orlipid derivative, covalent attachment of phosphotidylinositol,cross-linking, cyclization, disulfide bond formation, demethylation,formation of covalent crosslinks, formation of cystine, formation ofpyroglutamate, formylation, gamma carboxylation, glycosylation, GPIanchor formation, hydroxylation, iodination, methylation,myristoylation, oxidation, proteolytic processing, phosphorylation,prenylation, racemization, selenoylation, sulfation, transfer-RNAmediated addition of amino acids to proteins such as arginylation, andubiquitination.

Such protein modifications are well known to those of skill in the artand have been described in great detail in the scientific literature.Particularly common modifications, for example glycosylation, lipidattachment, sulfation, gamma-carboxylation of glutamic acid residues,hydroxylation and ADP-ribosylation, are described in most basic texts,such as Proteins—Structure and Molecular Properties 2nd Ed., T. E.Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold,Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson,ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol182:626-646 (1990); and Rattan et al., Ann NY Acad Sci 663:48-62 (1992).

The present invention further provides fragments of the variant proteinsin which the fragments contain one or more amino acid sequencevariations (e.g., substitutions, or truncations or extensions due tocreation or destruction of a stop codon) encoded by one or more SNPsdisclosed herein. The fragments to which the invention pertains,however, are not to be construed as encompassing fragments that havebeen disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14,16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or morecontiguous amino acid residues from a variant protein, wherein at leastone amino acid residue is affected by a SNP of the present invention,e.g., a variant amino acid residue encoded by a nonsynonymous nucleotidesubstitution at a cSNP position provided by the present invention. Thevariant amino acid encoded by a cSNP may occupy any residue positionalong the sequence of the fragment. Such fragments can be chosen basedon the ability to retain one or more of the biological activities of thevariant protein or the ability to perform a function, e.g., act as animmunogen. Particularly important fragments are biologically activefragments. Such fragments will typically comprise a domain or motif of avariant protein of the present invention, e.g., active site,transmembrane domain, or ligand/substrate binding domain. Otherfragments include, but are not limited to, domain or motif-containingfragments, soluble peptide fragments, and fragments containingimmunogenic structures. Predicted domains and functional sites arereadily identifiable by computer programs well known to those of skillin the art (e.g., PROSITE analysis). Current Protocols in ProteinScience, John Wiley & Sons, N.Y. (2002).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a varietyof ways, including but not limited to, in assays to determine thebiological activity of a variant protein, such as in a panel of multipleproteins for high-throughput screening; to raise antibodies or to elicitanother type of immune response; as a reagent (including the labeledreagent) in assays designed to quantitatively determine levels of thevariant protein (or its binding partner) in biological fluids; as amarker for cells or tissues in which it is preferentially expressed(either constitutively or at a particular stage of tissuedifferentiation or development or in a disease state); as a target forscreening for a therapeutic agent; and as a direct therapeutic agent tobe administered into a human subject. Any of the variant proteinsdisclosed herein may be developed into reagent grade or kit format forcommercialization as research products. Methods for performing the useslisted above are well known to those skilled in the art. See, e.g.,Molecular Cloning: A Laboratory Manual, Sambrook and Russell, ColdSpring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology:Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel,eds., Academic Press (1987).

In a specific embodiment of the invention, the methods of the presentinvention include detection of one or more variant proteins disclosedherein. Variant proteins are disclosed in Table 1 and in the SequenceListing as SEQ ID NOS:308-614. Detection of such proteins can beaccomplished using, for example, antibodies, small molecule compounds,aptamers, ligands/substrates, other proteins or protein fragments, orother protein-binding agents. Preferably, protein detection agents arespecific for a variant protein of the present invention and cantherefore discriminate between a variant protein of the presentinvention and the wild-type protein or another variant form. This cangenerally be accomplished by, for example, selecting or designingdetection agents that bind to the region of a protein that differsbetween the variant and wild-type protein, such as a region of a proteinthat contains one or more amino acid substitutions that is/are encodedby a non-synonymous cSNP of the present invention, or a region of aprotein that follows a nonsense mutation-type SNP that creates a stopcodon thereby leading to a shorter polypeptide, or a region of a proteinthat follows a read-through mutation-type SNP that destroys a stop codonthereby leading to a longer polypeptide in which a portion of thepolypeptide is present in one version of the polypeptide but not theother.

In another specific aspect of the invention, the variant proteins of thepresent invention are used as targets for diagnosing CVD or fordetermining predisposition to CVD in a human, for treating and/orpreventing CVD, or for predicting an individual's response to atreatment (particularly treatment or prevention of CVD), etc.Accordingly, the invention provides methods for detecting the presenceof, or levels of, one or more variant proteins of the present inventionin a cell, tissue, or organism. Such methods typically involvecontacting a test sample with an agent (e.g., an antibody, smallmolecule compound, or peptide) capable of interacting with the variantprotein such that specific binding of the agent to the variant proteincan be detected. Such an assay can be provided in a single detectionformat or a multi-detection format such as an array, for example, anantibody or aptamer array (arrays for protein detection may also bereferred to as “protein chips”). The variant protein of interest can beisolated from a test sample and assayed for the presence of a variantamino acid sequence encoded by one or more SNPs disclosed by the presentinvention. The SNPs may cause changes to the protein and thecorresponding protein function/activity, such as through non-synonymoussubstitutions in protein coding regions that can lead to amino acidsubstitutions, deletions, insertions, and/or rearrangements; formationor destruction of stop codons; or alteration of control elements such aspromoters. SNPs may also cause inappropriate post-translationalmodifications.

One preferred agent for detecting a variant protein in a sample is anantibody capable of selectively binding to a variant form of the protein(antibodies are described in greater detail in the next section). Suchsamples include, for example, tissues, cells, and biological fluidsisolated from a subject, as well as tissues, cells and fluids presentwithin a subject.

In vitro methods for detection of the variant proteins associated withCVD that are disclosed herein and fragments thereof include, but are notlimited to, enzyme linked immunosorbent assays (ELISAs),radioimmunoassays (RIA), Western blots, immunoprecipitations,immunofluorescence, and protein arrays/chips (e.g., arrays of antibodiesor aptamers). For further information regarding immunoassays and relatedprotein detection methods, see Current Protocols in Immunology, JohnWiley & Sons, N.Y., and Hage, “Immunoassays,” Anal Chem 15;71(12):294R-304R (June 1999).

Additional analytic methods of detecting amino acid variants include,but are not limited to, altered electrophoretic mobility, alteredtryptic peptide digest, altered protein activity in cell-based orcell-free assay, alteration in ligand or antibody-binding pattern,altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject byintroducing into the subject a labeled antibody (or other type ofdetection reagent) specific for a variant protein. For example, theantibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based onthe class or action of the protein. For example, proteins isolated fromhumans and their mammalian orthologs serve as targets for identifyingagents (e.g., small molecule drugs or antibodies) for use in therapeuticapplications, particularly for modulating a biological or pathologicalresponse in a cell or tissue that expresses the protein. Pharmaceuticalagents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compoundscan be developed that modulate protein function. For example, many SNPsdisclosed herein affect the amino acid sequence of the encoded protein(e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Suchalterations in the encoded amino acid sequence may affect proteinfunction, particularly if such amino acid sequence variations occur infunctional protein domains, such as catalytic domains, ATP-bindingdomains, or ligand/substrate binding domains. It is well established inthe art that variant proteins having amino acid sequence variations infunctional domains can cause or influence pathological conditions. Insuch instances, compounds (e.g., small molecule drugs or antibodies) canbe developed that target the variant protein and modulate (e.g., up- ordown-regulate) protein function/activity.

The therapeutic methods of the present invention further include methodsthat target one or more variant proteins of the present invention.Variant proteins can be targeted using, for example, small moleculecompounds, antibodies, aptamers, ligands/substrates, other proteins, orother protein-binding agents. Additionally, the skilled artisan willrecognize that the novel protein variants (and polymorphic nucleic acidmolecules) disclosed in Table 1 may themselves be directly used astherapeutic agents by acting as competitive inhibitors of correspondingart-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful indrug screening assays, in cell-based or cell-free systems. Cell-basedsystems can utilize cells that naturally express the protein, a biopsyspecimen, or cell cultures. In one embodiment, cell-based assays involverecombinant host cells expressing the variant protein. Cell-free assayscan be used to detect the ability of a compound to directly bind to avariant protein or to the corresponding SNP-containing nucleic acidfragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriatefragments thereof, can be used in high-throughput screening assays totest candidate compounds for the ability to bind and/or modulate theactivity of the variant protein. These candidate compounds can befurther screened against a protein having normal function (e.g., awild-type/non-variant protein) to further determine the effect of thecompound on the protein activity. Furthermore, these compounds can betested in animal or invertebrate systems to determine in vivoactivity/effectiveness. Compounds can be identified that activate(agonists) or inactivate (antagonists) the variant protein, anddifferent compounds can be identified that cause various degrees ofactivation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for theability to stimulate or inhibit interaction between the variant proteinand a target molecule that normally interacts with the protein. Thetarget can be a ligand, a substrate or a binding partner that theprotein normally interacts with (for example, epinephrine ornorepinephrine). Such assays typically include the steps of combiningthe variant protein with a candidate compound under conditions thatallow the variant protein, or fragment thereof, to interact with thetarget molecule, and to detect the formation of a complex between theprotein and the target or to detect the biochemical consequence of theinteraction with the variant protein and the target, such as any of theassociated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as solublepeptides, including Ig-tailed fusion peptides and members of randompeptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991);Houghten et al., Nature 354:84-86 (1991)) and combinatorialchemistry-derived molecular libraries made of D- and/or L-configurationamino acids; 2) phosphopeptides (e.g., members of random and partiallydegenerate, directed phosphopeptide libraries, see, e.g., Songyang etal., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal,monoclonal, humanized, anti-idiotypic, chimeric, and single chainantibodies as well as Fab, F(ab′)₂, Fab expression library fragments,and epitope-binding fragments of antibodies); and 4) small organic andinorganic molecules (e.g., molecules obtained from combinatorial andnatural product libraries).

One candidate compound is a soluble fragment of the variant protein thatcompetes for ligand binding. Other candidate compounds include mutantproteins or appropriate fragments containing mutations that affectvariant protein function and thus compete for ligand. Accordingly, afragment that competes for ligand, for example with a higher affinity,or a fragment that binds ligand but does not allow release, isencompassed by the invention.

The invention further includes other end point assays to identifycompounds that modulate (stimulate or inhibit) variant protein activity.The assays typically involve an assay of events in the signaltransduction pathway that indicate protein activity. Thus, theexpression of genes that are up or down-regulated in response to thevariant protein dependent signal cascade can be assayed. In oneembodiment, the regulatory region of such genes can be operably linkedto a marker that is easily detectable, such as luciferase.Alternatively, phosphorylation of the variant protein, or a variantprotein target, could also be measured. Any of the biological orbiochemical functions mediated by the variant protein can be used as anendpoint assay. These include all of the biochemical or biologicalevents described herein, in the references cited herein, incorporated byreference for these endpoint assay targets, and other functions known tothose of ordinary skill in the art.

Binding and/or activating compounds can also be screened by usingchimeric variant proteins in which an amino terminal extracellulardomain or parts thereof, an entire transmembrane domain or subregions,and/or the carboxyl terminal intracellular domain or parts thereof, canbe replaced by heterologous domains or subregions. For example, asubstrate-binding region can be used that interacts with a differentsubstrate than that which is normally recognized by a variant protein.Accordingly, a different set of signal transduction components isavailable as an end-point assay for activation. This allows for assaysto be performed in other than the specific host cell from which thevariant protein is derived.

The variant proteins are also useful in competition binding assays inmethods designed to discover compounds that interact with the variantprotein. Thus, a compound can be exposed to a variant protein underconditions that allow the compound to bind or to otherwise interact withthe variant protein. A binding partner, such as ligand, that normallyinteracts with the variant protein is also added to the mixture. If thetest compound interacts with the variant protein or its binding partner,it decreases the amount of complex formed or activity from the variantprotein. This type of assay is particularly useful in screening forcompounds that interact with specific regions of the variant protein.Hodgson, Bio/technology, 10(9), 973-80 (September 1992).

To perform cell-free drug screening assays, it is sometimes desirable toimmobilize either the variant protein or a fragment thereof, or itstarget molecule, to facilitate separation of complexes from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Any method for immobilizing proteins onmatrices can be used in drug screening assays. In one embodiment, afusion protein containing an added domain allows the protein to be boundto a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteinscan be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.Louis, Mo.) or glutathione derivatized microtitre plates, which are thencombined with the cell lysates (e.g., ³⁵S-labeled) and a candidatecompound, such as a drug candidate, and the mixture incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads can bewashed to remove any unbound label, and the matrix immobilized andradiolabel determined directly, or in the supernatant after thecomplexes are dissociated. Alternatively, the complexes can bedissociated from the matrix, separated by SDS-PAGE, and the level ofbound material found in the bead fraction quantitated from the gel usingstandard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilizedutilizing conjugation of biotin and streptavidin. Alternatively,antibodies reactive with the variant protein but which do not interferewith binding of the variant protein to its target molecule can bederivatized to the wells of the plate, and the variant protein trappedin the wells by antibody conjugation. Preparations of the targetmolecule and a candidate compound are incubated in the variantprotein-presenting wells and the amount of complex trapped in the wellcan be quantitated. Methods for detecting such complexes, in addition tothose described above for the GST-immobilized complexes, includeimmunodetection of complexes using antibodies reactive with the proteintarget molecule, or which are reactive with variant protein and competewith the target molecule, and enzyme-linked assays that rely ondetecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to thesedrug screening assays can be used to treat a subject with a disordermediated by the protein pathway, such as CVD. These methods of treatmenttypically include the steps of administering the modulators of proteinactivity in a pharmaceutical composition to a subject in need of suchtreatment.

The variant proteins, or fragments thereof, disclosed herein canthemselves be directly used to treat a disorder characterized by anabsence of, inappropriate, or unwanted expression or activity of thevariant protein. Accordingly, methods for treatment include the use of avariant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as“bait proteins” in a two-hybrid assay or three-hybrid assay to identifyother proteins that bind to or interact with the variant protein and areinvolved in variant protein activity. See, e.g., U.S. Pat. No.5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J BiolChem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924(1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO94/10300. Such variant protein-binding proteins are also likely to beinvolved in the propagation of signals by the variant proteins orvariant protein targets as, for example, elements of a protein-mediatedsignaling pathway. Alternatively, such variant protein-binding proteinsare inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of mosttranscription factors, which typically consist of separable DNA-bindingand activation domains. Briefly, the assay typically utilizes twodifferent DNA constructs. In one construct, the gene that codes for avariant protein is fused to a gene encoding the DNA binding domain of aknown transcription factor (e.g., GAL-4). In the other construct, a DNAsequence, from a library of DNA sequences, that encodes an unidentifiedprotein (“prey” or “sample”) is fused to a gene that codes for theactivation domain of the known transcription factor. If the “bait” andthe “prey” proteins are able to interact, in vivo, forming a variantprotein-dependent complex, the DNA-binding and activation domains of thetranscription factor are brought into close proximity. This proximityallows transcription of a reporter gene (e.g., LacZ) that is operablylinked to a transcriptional regulatory site responsive to thetranscription factor. Expression of the reporter gene can be detected,and cell colonies containing the functional transcription factor can beisolated and used to obtain the cloned gene that encodes the proteinthat interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind tothe variant proteins disclosed herein and fragments thereof. Suchantibodies may be used to quantitatively or qualitatively detect thevariant proteins of the present invention. As used herein, an antibodyselectively binds a target variant protein when it binds the variantprotein and does not significantly bind to non-variant proteins, i.e.,the antibody does not significantly bind to normal, wild-type, orart-known proteins that do not contain a variant amino acid sequence dueto one or more SNPs of the present invention (variant amino acidsequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPsthat create a stop codon, thereby causing a truncation of a polypeptideor SNPs that cause read-through mutations resulting in an extension of apolypeptide).

As used herein, an antibody is defined in terms consistent with thatrecognized in the art: they are multi-subunit proteins produced by anorganism in response to an antigen challenge. The antibodies of thepresent invention include both monoclonal antibodies and polyclonalantibodies, as well as antigen-reactive proteolytic fragments of suchantibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, anantibody of the present invention further includes any of a variety ofengineered antigen-binding molecules such as a chimeric antibody (U.S.Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad SciUSA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), ahumanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and 5,565,332),a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544(1989)), a bispecific antibody with two binding specificities (Segal etal., J Immunol Methods 248:1 (2001); Carter, J Immunol Methods 248:7(2001)), a diabody, a triabody, and a tetrabody (Todorovska et al., JImmunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer ortrimer), and a minibody.

Many methods are known in the art for generating and/or identifyingantibodies to a given target antigen. Harlow, Antibodies, Cold SpringHarbor Press, N.Y. (1989). In general, an isolated peptide (e.g., avariant protein of the present invention) is used as an immunogen and isadministered to a mammalian organism, such as a rat, rabbit, hamster ormouse. Either a full-length protein, an antigenic peptide fragment(e.g., a peptide fragment containing a region that varies between avariant protein and a corresponding wild-type protein), or a fusionprotein can be used. A protein used as an immunogen may benaturally-occurring, synthetic or recombinantly produced, and may beadministered in combination with an adjuvant, including but not limitedto, Freund's (complete and incomplete), mineral gels such as aluminumhydroxide, surface active substance such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin,dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology, whichimmortalizes cells secreting a specific monoclonal antibody. Kohler andMilstein, Nature 256:495 (1975). The immortalized cell lines can becreated in vitro by fusing two different cell types, typicallylymphocytes, and tumor cells. The hybridoma cells may be cultivated invitro or in vivo. Additionally, fully human antibodies can be generatedby transgenic animals. He et al., J Immunol 169:595 (2002). Fd phage andFd phagemid technologies may be used to generate and select recombinantantibodies in vitro. Hoogenboom and Chames, Immunol Today 21:371 (2000);Liu et al., J Mol Biol 315:1063 (2002). The complementarity-determiningregions of an antibody can be identified, and synthetic peptidescorresponding to such regions may be used to mediate antigen binding.U.S. Pat. No. 5,637,677.

Antibodies are preferably prepared against regions or discrete fragmentsof a variant protein containing a variant amino acid sequence ascompared to the corresponding wild-type protein (e.g., a region of avariant protein that includes an amino acid encoded by a nonsynonymouscSNP, a region affected by truncation caused by a nonsense SNP thatcreates a stop codon, or a region resulting from the destruction of astop codon due to read-through mutation caused by a SNP). Furthermore,preferred regions will include those involved in function/activityand/or protein/binding partner interaction. Such fragments can beselected on a physical property, such as fragments corresponding toregions that are located on the surface of the protein, e.g.,hydrophilic regions, or can be selected based on sequence uniqueness, orbased on the position of the variant amino acid residue(s) encoded bythe SNPs provided by the present invention. An antigenic fragment willtypically comprise at least about 8-10 contiguous amino acid residues inwhich at least one of the amino acid residues is an amino acid affectedby a SNP disclosed herein. The antigenic peptide can comprise, however,at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) ormore amino acid residues, provided that at least one amino acid isaffected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated bycoupling (i.e., physically linking) the antibody or an antigen-reactivefragment thereof to a detectable substance. Detectable substancesinclude, but are not limited to, various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, β-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin, and examples of suitable radioactive materialinclude ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents,are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,”Expert Rev Vaccines (1):53-9 (February 2003); Ross et al., “Anticancerantibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg,“Advancing role of radiolabeled antibodies in the therapy of cancer,”Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003;Ross et al., “Antibody-based therapeutics in oncology,” Expert RevAnticancer Ther 3(1):107-21 (February 2003); Cao et al., “Bispecificantibody conjugates in therapeutics,” Adv Drug Deliv Rev 55(2):171-97(February 2003); von Mehren et al., “Monoclonal antibody therapy forcancer,” Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001; Hudson etal., “Engineered antibodies,” Nat Med 9(1):129-34 (January 2003); Brekkeet al., “Therapeutic antibodies for human diseases at the dawn of thetwenty-first century,” Nat Rev Drug Discov 2(1):52-62 (January 2003);Erratum in: Nat Rev Drug Discov 2(3):240 (March 2003); Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Andreakos etal., “Monoclonal antibodies in immune and inflammatory diseases,” CurrOpin Biotechnol 13(6):615-20 (December 2002); Kellermann et al.,“Antibody discovery: the use of transgenic mice to generate humanmonoclonal antibodies for therapeutics,” Curr Opin Biotechnol13(6):593-7 (December 2002); Pini et al., “Phage display and colonyfilter screening for high-throughput selection of antibody libraries,”Comb Chem High Throughput Screen 5(7):503-10 (November 2002); Batra etal., “Pharmacokinetics and biodistribution of genetically engineeredantibodies,” Curr Opin Biotechnol 13(6):603-8 (December 2002); andTangri et al., “Rationally engineered proteins or antibodies with absentor reduced immunogenicity,” Curr Med Chem 9(24):2191-9 (December 2002).

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the presentinvention from a natural cell source or from recombinant host cells bystandard techniques, such as affinity chromatography orimmunoprecipitation. In addition, antibodies are useful for detectingthe presence of a variant protein of the present invention in cells ortissues to determine the pattern of expression of the variant proteinamong various tissues in an organism and over the course of normaldevelopment or disease progression. Further, antibodies can be used todetect variant protein in situ, in vitro, in a bodily fluid, or in acell lysate or supernatant in order to evaluate the amount and patternof expression. Also, antibodies can be used to assess abnormal tissuedistribution, abnormal expression during development, or expression inan abnormal condition, such as in CVD, or during treatment.Additionally, antibody detection of circulating fragments of thefull-length variant protein can be used to identify turnover. Antibodiesto the variant proteins of the present invention are also useful inpharmacogenomic analysis. Thus, antibodies against variant proteinsencoded by alternative SNP alleles can be used to identify individualsthat require modified treatment modalities.

Further, antibodies can be used to assess expression of the variantprotein in disease states such as in active stages of the disease or inan individual with a predisposition to a disease related to theprotein's function, such as CVD, or during the course of a treatmentregime. Antibodies specific for a variant protein encoded by aSNP-containing nucleic acid molecule of the present invention can beused to assay for the presence of the variant protein, such as todiagnose CVD or to predict an individual's response to a treatment orpredisposition/susceptibility to CVD, as indicated by the presence ofthe variant protein.

Antibodies are also useful as diagnostic tools for evaluating thevariant proteins in conjunction with analysis by electrophoreticmobility, isoelectric point, tryptic peptide digest, and other physicalassays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specificvariant protein has been correlated with expression in a specifictissue, antibodies that are specific for this protein can be used toidentify a tissue type.

Antibodies can also be used to assess aberrant subcellular localizationof a variant protein in cells in various tissues. The diagnostic usescan be applied, not only in genetic testing, but also in monitoring atreatment modality. Accordingly, where treatment is ultimately aimed atcorrecting the expression level or the presence of variant protein oraberrant tissue distribution or developmental expression of a variantprotein, antibodies directed against the variant protein or relevantfragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function,for example, by blocking the binding of a variant protein to a bindingpartner. These uses can also be applied in a therapeutic context inwhich treatment involves inhibiting a variant protein's function. Anantibody can be used, for example, to block or competitively inhibitbinding, thus modulating (agonizing or antagonizing) the activity of avariant protein. Antibodies can be prepared against specific variantprotein fragments containing sites required for function or against anintact variant protein that is associated with a cell or cell membrane.For in vivo administration, an antibody may be linked with an additionaltherapeutic payload such as a radionuclide, an enzyme, an immunogenicepitope, or a cytotoxic agent. Suitable cytotoxic agents include, butare not limited to, bacterial toxin such as diphtheria, and plant toxinsuch as ricin. The in vivo half-life of an antibody or a fragmentthereof may be lengthened by pegylation through conjugation topolyethylene glycol. Leong et al., Cytokine 16:106 (2001).

The invention also encompasses kits for using antibodies, such as kitsfor detecting the presence of a variant protein in a test sample. Anexemplary kit can comprise antibodies such as a labeled or labelableantibody and a compound or agent for detecting variant proteins in abiological sample; means for determining the amount, or presence/absenceof variant protein in the sample; means for comparing the amount ofvariant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing theSNP-containing nucleic acid molecules described herein. The term“vector” refers to a vehicle, preferably a nucleic acid molecule, whichcan transport a SNP-containing nucleic acid molecule. When the vector isa nucleic acid molecule, the SNP-containing nucleic acid molecule can becovalently linked to the vector nucleic acid. Such vectors include, butare not limited to, a plasmid, single or double stranded phage, a singleor double stranded RNA or DNA viral vector, or artificial chromosome,such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal elementwhere it replicates and produces additional copies of the SNP-containingnucleic acid molecules. Alternatively, the vector may integrate into thehost cell genome and produce additional copies of the SNP-containingnucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) orvectors for expression (expression vectors) of the SNP-containingnucleic acid molecules. The vectors can function in prokaryotic oreukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions thatare operably linked in the vector to the SNP-containing nucleic acidmolecules such that transcription of the SNP-containing nucleic acidmolecules is allowed in a host cell. The SNP-containing nucleic acidmolecules can also be introduced into the host cell with a separatenucleic acid molecule capable of affecting transcription. Thus, thesecond nucleic acid molecule may provide a trans-acting factorinteracting with the cis-regulatory control region to allowtranscription of the SNP-containing nucleic acid molecules from thevector. Alternatively, a trans-acting factor may be supplied by the hostcell. Finally, a trans-acting factor can be produced from the vectoritself. It is understood, however, that in some embodiments,transcription and/or translation of the nucleic acid molecules can occurin a cell-free system. The regulatory sequences to which theSNP-containing nucleic acid molecules described herein can be operablylinked include promoters for directing mRNA transcription. Theseinclude, but are not limited to, the left promoter from bacteriophage λ,the lac, TRP, and TAC promoters from E. coli, the early and latepromoters from SV40, the CMV immediate early promoter, the adenovirusearly and late promoters, and retrovirus long-terminal repeats.

In addition to control regions that promote transcription, expressionvectors may also include regions that modulate transcription, such asrepressor binding sites and enhancers. Examples include the SV40enhancer, the cytomegalovirus immediate early enhancer, polyomaenhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation andcontrol, expression vectors can also contain sequences necessary fortranscription termination and, in the transcribed region, aribosome-binding site for translation. Other regulatory control elementsfor expression include initiation and termination codons as well aspolyadenylation signals. A person of ordinary skill in the art would beaware of the numerous regulatory sequences that are useful in expressionvectors. See, e.g., Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

A variety of expression vectors can be used to express a SNP-containingnucleic acid molecule. Such vectors include chromosomal, episomal, andvirus-derived vectors, for example, vectors derived from bacterialplasmids, from bacteriophage, from yeast episomes, from yeastchromosomal elements, including yeast artificial chromosomes, fromviruses such as baculoviruses, papovaviruses such as SV40, Vacciniaviruses, adenoviruses, poxviruses, pseudorabies viruses, andretroviruses. Vectors can also be derived from combinations of thesesources such as those derived from plasmid and bacteriophage geneticelements, e.g., cosmids and phagemids. Appropriate cloning andexpression vectors for prokaryotic and eukaryotic hosts are described inSambrook and Russell, Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, N.Y. (2000).

The regulatory sequence in a vector may provide constitutive expressionin one or more host cells (e.g., tissue specific expression) or mayprovide for inducible expression in one or more cell types such as bytemperature, nutrient additive, or exogenous factor, e.g., a hormone orother ligand. A variety of vectors that provide constitutive orinducible expression of a nucleic acid sequence in prokaryotic andeukaryotic host cells are well known to those of ordinary skill in theart.

A SNP-containing nucleic acid molecule can be inserted into the vectorby methodology well-known in the art. Generally, the SNP-containingnucleic acid molecule that will ultimately be expressed is joined to anexpression vector by cleaving the SNP-containing nucleic acid moleculeand the expression vector with one or more restriction enzymes and thenligating the fragments together. Procedures for restriction enzymedigestion and ligation are well known to those of ordinary skill in theart.

The vector containing the appropriate nucleic acid molecule can beintroduced into an appropriate host cell for propagation or expressionusing well-known techniques. Bacterial host cells include, but are notlimited to, Escherichia coli, Streptomyces spp., and Salmonellatyphimurium. Eukaryotic host cells include, but are not limited to,yeast, insect cells such as Drosophila spp., animal cells such as COSand CHO cells, and plant cells.

As described herein, it may be desirable to express the variant peptideas a fusion protein. Accordingly, the invention provides fusion vectorsthat allow for the production of the variant peptides. Fusion vectorscan, for example, increase the expression of a recombinant protein,increase the solubility of the recombinant protein, and aid in thepurification of the protein by acting, for example, as a ligand foraffinity purification. A proteolytic cleavage site may be introduced atthe junction of the fusion moiety so that the desired variant peptidecan ultimately be separated from the fusion moiety. Proteolytic enzymessuitable for such use include, but are not limited to, factor Xa,thrombin, and enterokinase. Typical fusion expression vectors includepGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs,Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuseglutathione S-transferase (GST), maltose E binding protein, or proteinA, respectively, to the target recombinant protein. Examples of suitableinducible non-fusion E. coli expression vectors include pTrc (Amann etal., Gene 69:301-315 (1988)) and pET 11d (Studier et al., GeneExpression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host byproviding a genetic background wherein the host cell has an impairedcapacity to proteolytically cleave the recombinant protein (S.Gottesman, Gene Expression Technology: Methods in Enzymology185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequenceof the SNP-containing nucleic acid molecule of interest can be alteredto provide preferential codon usage for a specific host cell, forexample, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).

The SNP-containing nucleic acid molecules can also be expressed byexpression vectors that are operative in yeast. Examples of vectors forexpression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari etal., EMBO J. 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2(Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed ininsect cells using, for example, baculovirus expression vectors.Baculovirus vectors available for expression of proteins in culturedinsect cells (e.g., Sf 9 cells) include the pAc series (Smith et al.,Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al.,Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acidmolecules described herein are expressed in mammalian cells usingmammalian expression vectors. Examples of mammalian expression vectorsinclude pCDM8 (B. Seed, Nature 329:840 (1987)) and pMT2PC (Kaufman etal., EMBO J 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containingnucleic acid molecules described herein are cloned into the vector inreverse orientation, but operably linked to a regulatory sequence thatpermits transcription of antisense RNA. Thus, an antisense transcriptcan be produced to the SNP-containing nucleic acid sequences describedherein, including both coding and non-coding regions. Expression of thisantisense RNA is subject to each of the parameters described above inrelation to expression of the sense RNA (regulatory sequences,constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing thevectors described herein. Host cells therefore include, for example,prokaryotic cells, lower eukaryotic cells such as yeast, othereukaryotic cells such as insect cells, and higher eukaryotic cells suchas mammalian cells.

The recombinant host cells can be prepared by introducing the vectorconstructs described herein into the cells by techniques readilyavailable to persons of ordinary skill in the art. These include, butare not limited to, calcium phosphate transfection,DEAE-dextran-mediated transfection, cationic lipid-mediatedtransfection, electroporation, transduction, infection, lipofection, andother techniques such as those described in Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press, N.Y. (2000).

Host cells can contain more than one vector. Thus, differentSNP-containing nucleotide sequences can be introduced in differentvectors into the same cell. Similarly, the SNP-containing nucleic acidmolecules can be introduced either alone or with other nucleic acidmolecules that are not related to the SNP-containing nucleic acidmolecules, such as those providing trans-acting factors for expressionvectors. When more than one vector is introduced into a cell, thevectors can be introduced independently, co-introduced, or joined to thenucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introducedinto cells as packaged or encapsulated virus by standard procedures forinfection and transduction. Viral vectors can be replication-competentor replication-defective. In the case in which viral replication isdefective, replication can occur in host cells that provide functionsthat complement the defects.

Vectors generally include selectable markers that enable the selectionof the subpopulation of cells that contain the recombinant vectorconstructs. The marker can be inserted in the same vector that containsthe SNP-containing nucleic acid molecules described herein or may be ina separate vector. Markers include, for example, tetracycline orampicillin-resistance genes for prokaryotic host cells, anddihydrofolate reductase or neomycin resistance genes for eukaryotic hostcells. However, any marker that provides selection for a phenotypictrait can be effective.

While the mature variant proteins can be produced in bacteria, yeast,mammalian cells, and other cells under the control of the appropriateregulatory sequences, cell-free transcription and translation systemscan also be used to produce these variant proteins using RNA derivedfrom the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult toachieve with multi-transmembrane domain containing proteins such asG-protein-coupled receptors (GPCRs), appropriate secretion signals canbe incorporated into the vector. The signal sequence can be endogenousto the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the proteincan be isolated from the host cell by standard disruption procedures,including freeze/thaw, sonication, mechanical disruption, use of lysingagents, and the like. The variant protein can then be recovered andpurified by well-known purification methods including, for example,ammonium sulfate precipitation, acid extraction, anion or cationicexchange chromatography, phosphocellulose chromatography,hydrophobic-interaction chromatography, affinity chromatography,hydroxylapatite chromatography, lectin chromatography, or highperformance liquid chromatography.

It is also understood that, depending upon the host cell in whichrecombinant production of the variant proteins described herein occurs,they can have various glycosylation patterns, or may benon-glycosylated, as when produced in bacteria. In addition, the variantproteins may include an initial modified methionine in some cases as aresult of a host-mediated process.

For further information regarding vectors and host cells, see CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins describedherein have a variety of uses. For example, the cells are useful forproducing a variant protein that can be further purified into apreparation of desired amounts of the variant protein or fragmentsthereof. Thus, host cells containing expression vectors are useful forvariant protein production.

Host cells are also useful for conducting cell-based assays involvingthe variant protein or variant protein fragments, such as thosedescribed above as well as other formats known in the art. Thus, arecombinant host cell expressing a variant protein is useful forassaying compounds that stimulate or inhibit variant protein function.Such an ability of a compound to modulate variant protein function maynot be apparent from assays of the compound on the native/wild-typeprotein, or from cell-free assays of the compound. Recombinant hostcells are also useful for assaying functional alterations in the variantproteins as compared with a known function.

Genetically-engineered host cells can be further used to producenon-human transgenic animals. A transgenic animal is preferably anon-human mammal, for example, a rodent, such as a rat or mouse, inwhich one or more of the cells of the animal include a transgene. Atransgene is exogenous DNA containing a SNP of the present inventionwhich is integrated into the genome of a cell from which a transgenicanimal develops and which remains in the genome of the mature animal inone or more of its cell types or tissues. Such animals are useful forstudying the function of a variant protein in vivo, and identifying andevaluating modulators of variant protein activity. Other examples oftransgenic animals include, but are not limited to, non-human primates,sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-humanmammals such as cows and goats can be used to produce variant proteinswhich can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containingnucleic acid molecule into the male pronuclei of a fertilized oocyte,e.g., by microinjection or retroviral infection, and allowing the oocyteto develop in a pseudopregnant female foster animal. Any nucleic acidmolecules that contain one or more SNPs of the present invention canpotentially be introduced as a transgene into the genome of a non-humananimal.

Any of the regulatory or other sequences useful in expression vectorscan form part of the transgenic sequence. This includes intronicsequences and polyadenylation signals, if not already included. Atissue-specific regulatory sequence(s) can be operably linked to thetransgene to direct expression of the variant protein in particularcells or tissues.

Methods for generating transgenic animals via embryo manipulation andmicroinjection, particularly animals such as mice, have becomeconventional in the art and are described, for example, in U.S. Pat.Nos. 4,736,866 and 4,870,009, both by Leder et al.; U.S. Pat. No.4,873,191 by Wagner et al., and in B. Hogan, Manipulating the MouseEmbryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similarmethods are used for production of other transgenic animals. Atransgenic founder animal can be identified based upon the presence ofthe transgene in its genome and/or expression of transgenic mRNA intissues or cells of the animals. A transgenic founder animal can then beused to breed additional animals carrying the transgene. Moreover,transgenic animals carrying a transgene can further be bred to othertransgenic animals carrying other transgenes. A transgenic animal alsoincludes a non-human animal in which the entire animal or tissues in theanimal have been produced using the homologously recombinant host cellsdescribed herein.

In another embodiment, transgenic non-human animals can be producedwhich contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinasesystem of bacteriophage P1. Lakso et al., PNAS 89:6232-6236 (1992).Another example of a recombinase system is the FLP recombinase system ofS. cerevisiae. O'Gorman et al., Science 251:1351-1355 (1991). If acre/loxP recombinase system is used to regulate expression of thetransgene, animals containing transgenes encoding both the Crerecombinase and a selected protein are generally needed. Such animalscan be provided through the construction of “double” transgenic animals,e.g., by mating two transgenic animals, one containing a transgeneencoding a selected variant protein and the other containing a transgeneencoding a recombinase.

Clones of the non-human transgenic animals described herein can also beproduced according to the methods described, for example, in I. Wilmutet al., Nature 385:810-813 (1997) and PCT International Publication Nos.WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell)from the transgenic animal can be isolated and induced to exit thegrowth cycle and enter G_(o) phase. The quiescent cell can then befused, e.g., through the use of electrical pulses, to an enucleatedoocyte from an animal of the same species from which the quiescent cellis isolated. The reconstructed oocyte is then cultured such that itdevelops to morula or blastocyst and then transferred to pseudopregnantfemale foster animal. The offspring born of this female foster animalwill be a clone of the animal from which the cell (e.g., a somatic cell)is isolated.

Transgenic animals containing recombinant cells that express the variantproteins described herein are useful for conducting the assays describedherein in an in vivo context. Accordingly, the various physiologicalfactors that are present in vivo and that could influence ligand orsubstrate binding, variant protein activation, signal transduction, orother processes or interactions, may not be evident from in vitrocell-free or cell-based assays. Thus, non-human transgenic animals ofthe present invention may be used to assay in vivo variant proteinfunction as well as the activities of a therapeutic agent or compoundthat modulates variant protein function/activity or expression. Suchanimals are also suitable for assessing the effects of null mutations(i.e., mutations that substantially or completely eliminate one or morevariant protein functions).

For further information regarding transgenic animals, see Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol 13(6):625-9 (Dec. 2002); Petters et al.,“Transgenic animals as models for human disease,” Transgenic Res9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenicanimals in understanding molecular mechanisms of toxicity,” J PharmPharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant proteinproduction in transgenic animals,” Curr Opin Biotechnol 7(5):536-40(October 1996); Houdebine, “Transgenic animal bioreactors,” TransgenicRes 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creatingtransgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl etal., “Artificial chromosome vectors and expression of complex proteinsin transgenic animals,” Theriogenology 59(1):107-13 (January 2003).

EXAMPLES

The following examples are offered to illustrate, but not limit, theclaimed invention.

Example 1 SNP rs197922 in GOSR2 is Associated with Hypertension

Overview

A missense SNP in GOSR2 (Lys67Arg, rs197922) was analyzed forassociation with hypertension and blood pressure. Logistic and linearregression was used to test the association of the GOSR2SNP withhypertension and blood pressure among 3,528 blacks and 9,861 whites fromthe Atherosclerosis Risk in Communities (ARIC) study. Race-specificregression models of hypertension were adjusted for age and gender.Adjustments were made for anti-hypertensive medication use when testingthe association with blood pressure.

The Lys67 allele of GOSR2 was associated with increased hypertensionrisk in whites (adjusted odds ratio=1.09, P=0.01) (in blacks, adjustedodds ratio=0.96, P=0.47). The Lys67 allele was also associated withsystolic blood pressure (SBP) in both races (adjusted β=0.87, P<0.001and adjusted β=1.05, P=0.05 for whites and blacks, respectively). Thisallele was also associated with SBP in white participants of the Women'sHealth Study (P=0.11).

See Meyer et al., Am J Hypertens. 2009 February; 22(2):163-8,incorporated herein by reference in its entirety.

Methods

Atherosclerosis Risk in Communities Study (ARIC)

Study Population

The Atherosclerosis Risk in Communities (ARIC) study is a longitudinalcohort study of atherosclerosis, cardiovascular disease, and their riskfactors. The population and study methods have been described in detailelsewhere.¹² Briefly, from 1987 to 1989, 15,792 participants between theages of 45 to 64 were sampled from four study sites in the UnitedStates: Forsyth County, N.C.; Jackson, Miss.; suburban Minneapolis,Minn.; and Washington County, Md. At baseline and in three-yearintervals following the baseline visit (1990-1992, 1993-1995, and1996-1998) participants were interviewed and underwent a brief clinicalexamination. The study was approved by institutional review boards fromeach field center and written informed consent was obtained fromparticipants before each examination. Follow-up examinations weresupplemented with annual telephone interviews.

In the current analysis, individuals from races other than white orblack (n=48) or blacks from Minnesota and Washington County (n=55) wereexcluded due to small numbers. Those who refused to participate ingenetic studies (n=44) were also excluded. Since incident CHD was theoutcome used in the primary study in which GOSR2 was selected, and sinceresults for hypertension were similar with or without exclusion forprevalent CHD, participants were excluded for prevalent CHD (n=762),missing CHD (337), or prevalent stroke (n=331), leaving 14,215participants (10,401 whites, 3,814 blacks, 6,146 males and 8,069females). During 196,069 person-years of follow-up (mean 13.8 years),1,747 (12%) of the 14,215 ARIC participants in this analysis had anincident CHD event. For the present analysis of GOSR2 and hypertension,those missing information for GOSR2 genotype (n=826) were furtherexcluded, resulting in 13,389 participants (9,861 whites, 3,528 blacks,5,787 males and 7,602 females). At baseline, 4,416 of the 13,389participants (33%) reported prevalent hypertension.

Measurements

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) weremeasured after resting for 5 minutes in the seated position using arandom-zero sphygmomanometer. Second and third readings were averaged toderive the blood pressure measures used here. Hypertension was definedas a SBP of 140 mmHg or greater, a DBP of 90 mmHg or greater, or use ofblood pressure lowering medications in the past two weeks. Waistcircumference was measured once at the umbilicus with an anthropometrictape. Levels of fasting triglycerides,¹³ total cholesterol,¹⁴ highdensity lipoprotein cholesterol (HDL),¹⁵ and glucose¹⁶ were measured inblood samples using standard methods that have been reported previously.Low density lipoprotein (LDL) cholesterol was calculated using theFriedewald formula.¹⁷ Carotid artery (CA) intima media thickness (IMT)was measured using high-resolution B-mode ultrasound followingstructured protocols as described elsewhere.^(18,19) The mean ofmeasurements taken at six carotid artery sites were used. High IMT wasdefined as ≧75% the separately for men and women. Diabetes was definedas a fasting blood glucose of 126 mg/dL or more, a non-fasting bloodglucose of 200 mg/dL or more, self-reported diabetes, or use of diabetesmedications in the past two weeks. Incident CHD was defined bydocumented MI, unstable angina, sudden coronary death, or non-electivecardiovascular surgical procedures. Incident CHD events were determinedthrough 2003. Follow-up time for CHD events was calculated from the dateof the baseline visit to the date of the first CHD event for CHD casesor until either Dec. 31, 2003 or the last date of contact for those whodid not have a CHD event. Genotypes in the ARIC participants weredetermined by an oligonucleotide ligation procedure that combined PCRamplification of target sequences from 3 ng of genomic DNA withsubsequent allele-specific oligonucleotide ligation.²⁰ The ligationproducts of the two alleles were separated by hybridization to productspecific oligonucleotides, each coupled to spectrally distinctLuminex100 xMAP microspheres (Luminex, Austin, Tex.). The capturedproducts were fluorescently labeled with streptavidin R-phycoerythrin(Prozyme, San Leandro, Calif.), sorted on the basis of microspherespectrum, and detected by a Luminex100 instrument.

SNP Selection

SNPs were identified that were associated with CHD in two antecedentcase control studies of MI. Briefly, 20,009 SNPs (in 9,874 Entrez orEnsembl genes) were tested in one case control study (475 cases of MIand 649 non-MI controls). The 1,548 SNPs that were associated with MI inthis first study (P<0.1), were then tested in a second case-controlstudy of MI (793 MI cases and 1,000 healthy controls). Further detailsof the antecedent case control studies can be found in otherreferences.²¹⁻²³ 77 SNPs were found that were associated with MI (P<0.1)and had the same risk alleles in both studies (Table 7). The riskalleles of 72 of these 77 SNPs were then tested for their associationwith time to incident CHD in ARIC using Cox proportional hazards models,where the SNPs were modeled in an additive manner along with gender andage (five of the 77 SNPs were not tested in ARIC because good qualitymultiplex assays could not be made for them). One of the SNPs that wasassociated with CHD was in GOSR2 (Lys67Arg, rs197922). Complete resultsfor the association tests between incident CHD in ARIC for 34 of the 72SNPs are reported in Morrison et al.²³ and Bare et al.²²

Statistics

Means and standard deviations or frequencies and percents werecalculated for continuous and categorical variables, respectively.Triglyceride levels were natural-log transformed for comparison of meanlevels by genotype. Mean systolic blood pressure (SBP) and diastolicblood pressure (DBP) were calculated excluding participants who wereusing anti-hypertensive medications. Differences in means or frequenciesby genotype were determined using the F-test or chi-square test asappropriate for continuous and categorical variables. In all regressionmodels, the GOSR2SNP was coded in an additive manner. Linear regressionwas used to analyze the association between the GOSR2SNP and thecontinuous variables, such as SBP and DBP. Logistic regression was usedto analyze the association between the GOSR2SNP and prevalenthypertension, elevated SBP, DBP, and IMT (≧75% tile). Linear andlogistic regression models were adjusted for age and gender. Regressionmodels of SBP and DBP were additionally adjusted for use ofanti-hypertensive medications. Since additive models have been shown toperform well even when the underlying inheritance model is recessive ordominant,^(24,25) and since there is no previous literature indicatingan inheritance model for the GOSR2SNP and hypertension, estimates forthe additive model for GOSR2 were reported. Differences in results bygender were evaluated using the likelihood ratio test. No significantdifferences by gender were detected, so gender-specific results are notpresented. Power to detect an association between the GOSR2SNP andhypertension with OR of 1.1 was 79% among white participants of ARIC and45% among black participants.

Results

GOSR2 genotype frequencies differed by race (P<0.001; whites: ArgArg43.2%, LysArg 44.6%, LysLys 12.2%; blacks: ArgArg 48.1%, LysArg 42.4%,LysLys 9.5%) but were consistent with Hardy-Weinberg expectations forboth whites (Pearson chisquare=1.57; P=0.21) and blacks (Pearsonchisquare=0.08; P=0.78).

Means and percentages for the demographic and clinical variables atbaseline are presented in Table 8 according to race and genotype. MeanSBP (P=0.004) and DBP (P=0.09) among those not using anti-hypertensivemedications, waist circumference (P=0.05), and CA IMT (P=0.02) differedby genotype among whites (there were no differences among blacks). TheGOSR2SNP was significantly associated with SBP in both whites (β=0.87,P<0.001) and blacks (β=1.05, P=0.05) after adjustment for age, gender,and use of anti-hypertensive medications. The GOSR2SNP was alsoassociated with DBP among whites after adjustment (β=0.37, P=0.01) (inblacks, after adjustment, β=0.44, P=0.14). Prevalent hypertension atbaseline also differed by genotype among whites (P<0.01) (among blacks,P=0.66).

The risk associated with the GOSR2SNP and blood pressure was assessedusing dichotomized SBP and DBP variables (>75% tile). An association wasfound between the Lys67 allele of the GOSR2SNP and elevated SBP (OR:1.08; 95% CI: 1.00 to 1.15) and elevated DBP (OR: 1.08; 95% CI: 1.01 to1.16) among whites (Table 9). The risk associated with GOSR2 and adichotomized IMT variable was also assessed and found to be associatedwith elevated CA IMT (OR: 1.09; 95% CI: 1.01 to 1.17) among whites. Theeffect sizes were similar across measures of high blood pressure andconsistent with the comparison of means by genotype in Table 8. In agenotypic assessment of the GOSR2 variant associated with hypertensionamong whites, the OR for LysArg compared to ArgArg and LysLys comparedto ArgArg were similar in magnitude (OR: 1.18; 95% CI: 1.06 to 1.30 andOR: 1.13; 95% CI: 0.97 to 1.31, respectively), consistent with adominant inheritance model for GOSR2 and hypertension in whites.

Discussion

The GOSR2Lys67Arg SNP (rs197922) was analyzed for association withhypertension in the ARIC study and it was found that the Lys67 allelewas associated with hypertension, as well as with elevated SBP and DBP.The Lys67 allele had been shown to be associated with increased risk ofCHD in antecedent studies (Table 7). In this example, the GOSR2Lys67allele was found to be associated with increased occurrence ofhypertension in white participants in the ARIC study (additive OR: 1.09;95% CI: 1.02 to 1.17; dominance OR: 1.16; 95% CI 1.06 to 1.28). ThisLys67 allele was also found to be associated with quantitative traitssuch as SBP, DBP, and CA IMT among whites in ARIC. Linear regressionrevealed that the Lys67 allele was also associated with SBP among blackparticipants of ARIC after adjusting for age, gender, and use ofanti-hypertensive medication.

The association between the Lys67 allele of GOSR2 and blood pressure wasalso tested in white participants of the Women's Health Study (WHS).²⁶Allele frequencies of Lys67Arg in the white participants of WHS weresimilar to those of white participants of ARIC (data not shown). Anassociation with increased SBP was observed for the Lys67 allele ofGOSR2 in this WHS population (OR=1.03; P=0.04, in an ordinal logisticregression of nine SBP categories after adjusting for age) (OR=1.03 andP=0.11 after additionally adjusting for use of anti-hypertensivemedications).

GOSR2

GOSR2 codes for a vesicular N-ethylmaleimide sensitive factor attachmentprotein receptor (v-SNARE) that is involved in intra-Golgi traffickingof vesicles.²⁹ v-SNAREs such as GOSR2 interact with target-localizedSNAREs (t-SNAREs) to allow directed movement of macromolecules, such asinsulin, leptin, and angiotensinogen, between Golgi compartments.³⁰⁻³²GOSR2 is expressed in multiple tissues.⁷

GOSR2 is located under linkage peaks with hypertension on humanchromosome 17,⁸⁻¹⁰ as well as the syntenic rat chromosome 10, and murinechromosome 11.¹¹ Despite the evidence in both humans and animal modelsfor the region's contribution to blood pressure and risk ofhypertension, an association between GOSR2 and hypertension has notpreviously been reported. Other genes in this region may be consideredcandidates for essential hypertension, but of these only MYL4 (myosinlight polypeptide 4) is in a LD region with the GOSR2 rs197922polymorphism. Using data from the International HapMap Project,²⁸ oneSNP (rs16941671) from MYL4 was in moderate LD with GOSR2 rs197922(r²=0.19; D′=0.87) in the CEPH (Utah residents with ancestry fromnorthern and western Europe) population.

Since GOSR2 codes for a vesicular membrane protein involved inintra-Golgi protein trafficking, the results described here indicatethat protein processing in the Golgi influences blood pressure levelsand risk of hypertension, and altered regulation of protein trafficking(such as may be attributable to a SNP such as rs197922 that can causealternative amino acids to be encoded) within the Golgi may contributeto blood pressure and essential hypertension.

REFERENCES

(Reference Numbers Corresponds to Example 1 Only, with the Exception ofReference Numbers 33 and 34 which Correspond to Table 7)

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A SNARE    involved in protein transport through the Golgi apparatus. Nature.    1997; 389:881-884.-   8. Levy D, DeStefano A L, Larson M G, O'Donnell, C J, Lifton R P,    Gavras H, Cupples L A, Myers R H. Evidence for a gene influencing    blood pressure on chromosome 17. Genome scan linkage results for    longitudinal blood pressure phenotypes in subjects from the    Framingham heart study. Hypertension. 2000; 36:477-483.-   9. Baima J, Nicolaou M, Schwartz F, DeStefano A L, Manolis A, Gavras    I, Laffer C, Elijovich F, Farrer L, Baldwin C T, Gavras H. Evidence    for linkage between essential hypertension and a putative locus on    human chromosome 17. Hypertension. 1999; 34:4-7.-   10. Julier C, Delepine M, Keavney B, Terwilliger J, Davis S, Weeks D    E, Bui T, Jeunemaitre X, Velho G, Froguel P, Ratcliffe P, Corvol P,    Soubrier F, Lathrop G M. Genetic susceptibility for human familial    essential hypertension in a region of homology with blood pressure    linkage on rat chromosome 10. Hum Mol. Genet. 1997; 6:2077-2085.-   11. Knight J, Munroe P B, Pembroke J C, Caulfield M J. Human    chromosome 17 in essential hypertension. Ann Hum Genet. 2003;    67:193-206.-   12. The Atherosclerosis Risk in Communities (ARIC) study: Design and    objectives. The ARIC investigators. Am J Epidemiol. 1989;    129:687-702.-   13. Nagele U, Hagele E O, Sauer G, Wiedemann E, Lehmann P, Wahlefeld    A W, Gruber W. Reagent for the enzymatic determination of serum    total triglycerides with improved lipolytic efficiency. Journal of    Clinical Chemistry & Clinical Biochemistry. 1984; 22:165-174.-   14. Siedel J, Hagele E O, Ziegenhorn J, Wahlefeld A W. Reagent for    the enzymatic determination of serum total cholesterol with improved    lipolytic efficiency. Clin Chem. 1983; 29:1075-1080.-   15. Warnick G R, Benderson J, Albers J J. Dextran sulfate-Mg2+    precipitation procedure for quantitation of high-density-lipoprotein    cholesterol. Clin Chem. 1982; 28:1379-1388.-   16. Operations manual no. 10: Clinical chemistry determinations,    version 1.0.; Chapel Hill: ARIC Coordinating Center, School of    Public Health, University of North Carolina. 1987.-   17. Friedewald W T, Levy R I, Fredrickson D S. Estimation of the    concentration of low-density lipoprotein cholesterol in plasma,    without use of the preparative ultracentrifuge. Clin Chem. 1972;    18:499-502.-   18. Anonymous. High-resolution B-mode ultrasound scanning methods in    the Atherosclerosis Risk in Communities study (ARIC). The ARIC study    group. Journal of Neuroimaging. 1991; 1:68-73.-   19. Stevens J, Tyroler H A, Cai J, Paton C C, Folsom A R, Tell G S,    Schreiner P J, Chambless L E. Body weight change and carotid artery    wall thickness. The Atherosclerosis Risk in Communities (ARIC)    study. Am J Epidemiol. 1998; 147:563-573.-   20. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z,    Arellano A R, Lumley T, Rice K, Iakoubova O, Luke M M, Young B A,    Malloy M J, Kane J P, Ellis S G, Tracy R P, Devlin J J, Psaty B M.    Association of gene variants with incident myocardial infarction in    the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol.    2008:28:173-179.-   21. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M,    Iakoubova O A, Pullinger C R, Cassano J, Aouizerat B E, Fenwick R G,    Reitz R E, Catanese J J, Leong D U, Zellner C, Sninsky J J, Topol E    J, Devlin J J, Kane J P. Identification of four gene variants    associated with myocardial infarction. Am J Hum Genet. 2005;    77:596-605.-   22. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M,    Iakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S,    Willerson J T, Devlin J J, Boerwinkle E. Five common gene variants    identify elevated genetic risk for coronary heart disease. Genetics    in Medicine. 2007; 9:682-689.-   23. Morrison A C, Bare L A, Chambless L E, Ellis S G, Malloy M, Kane    J P, Pankow J S, Devlin J J, Willerson J T, Boerwinkle E. Prediction    of coronary heart disease risk using a genetic risk score: The    Atherosclerosis Risk in Communities study. Am J Epidemiol. 2007;    166:28-35.-   24. Horvath S, Xu X, Laird N M. The family based association test    method: Strategies for studying general genotype—phenotype    associations. European Journal of Human Genetics. 2001; 9:301-306.-   25. Balding D J. A tutorial on statistical methods for population    association studies. Nature Reviews Genetics. 2006; 7:781-791.-   26. Rexrode K M, Lee I M, Cook N R, Hennekens C H, Buring J E.    Baseline characteristics of participants in the Women's Health    Study. Journal of Womens Health & Gender-Based Medicine. 2000;    9:19-27.-   27. 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Example 2 Identification of Five SNPs in Four Genes that are Associatedwith Myocardial Infarction

Overview

17,576 SNPs that could affect gene function or expression were analyzedfor association with MI. The testing of these SNPs was staged in threecase-control studies of MI. In the first study (762 cases, 857controls), 17,576 SNPs were tested and 1,949 SNPs were found that wereassociated with MI (P<0.05). These 1,949 SNPs were tested in a secondstudy (579 cases and 1159 controls) and it was found that 24 of theseSNPs were associated with MI (1-sided P<0.05) and had the same riskalleles in the first and second study. Finally, these 24 SNPs weretested in a third study (475 cases and 619 controls) and it was foundthat 5 of these SNPs, which are located in 4 genes (ENO1, FXN (2 SNPs),HLA-DPB2, and LPA), were associated with MI in the third study (1-sidedP<0.05), and had the same risk alleles in all three studies.

Thus, 5 SNPs were identified that are associated with MI.

See Shiffman et al., PLoS ONE. 2008 Aug. 6; 3(8):e2895, incorporatedherein by reference in its entirety.

Methods

Objectives

To identify genetic polymorphisms associated with MI, three case-controlstudies comprising cases with a history of MI and controls without ahistory of MI were interrogated. The first two case-control studies(Study 1 and Study 2) identified SNPs associated with MI. The hypothesesthat these SNPs are associated with MI were tested in Study 3. Theallele frequency of each SNP was determined in pools of case and controlDNA prior to determining the genotype of a smaller number of SNPs forall individual DNA samples.

Participants

Participants in Study 1 and Study 2 were enrolled between July 1989 andMay 2005 by the University of California, San Francisco (UCSF) GenomicResource in Arteriosclerosis. UCSF samples received at the Celeragenotyping facility by May 2004 were considered for inclusion inStudy 1. Samples that arrived past that date were considered for Study2. Cases in Study 1 and Study 2 included patients who had undergonediagnostic or interventional cardiac catheterization and patients of theUCSF Lipid Clinic. Controls were enrolled by the UCSF Genomic Resourcein Arteriosclerosis and included UCSF staff, patients of UCSF Clinics,and senior citizens who participated in physical activities at regionalcommunity centers and events for senior citizens. A history of MI forStudy 1 cases was verified by a clinical chart review or by TheInternational Classification of Diseases, 9^(th) Revision (ICD9) codes410 or 411 in the patient records. MI status for Study 2 cases wasdetermined by ICD9 codes 410 or 411 or by a self-reported history of MI.To characterize the accuracy of these self-reported histories, medicalrecord review for a sample of Study 2 cases resulted in verification ofthe self-reported MI status for 98% of the sample (verification byelectrocardiogram, cardiac enzymes or imaging). Controls had no historyof MI, diabetes or symptomatic vascular disease. All participants ofStudy 1 and Study 2 chose Caucasian as their ethnicity in response to amultiple-choice questionnaire.

Participants in Study 3 were patients of the Cleveland Clinic Foundation(CCF) Heart Center who had undergone diagnostic or interventionalcardiac catheterization between July 2001 and March 2003 and enrolled inthe Genebank at Cleveland Clinic Study. A history of MI was verified byelectrocardiogram, cardiac enzymes, or perfusion imaging. Controls hadless than 50% coronary luminal narrowing. All participants in Study-3selected North European, Eastern European, or ‘other Caucasian’ as thedescription of both their mother and father on the enrollmentquestionnaire. The demographic and risk factor characteristics of theparticipants in the 3 studies are presented in Table 11.

SNP Selection

The 17,576 SNPs investigated in Study 1 are located in 10,152 genes.These SNPs could potentially affect gene function or expression. Most(65%) of these SNPs were missense, nonsense, or were located in acceptorand donor splice sites. Other SNPs were located in transcription factorbinding sites, microRNA binding sites, exon splice enhancer and silencersites, or in untranslated regions of mRNA.

Allele Frequency and Genotype Determination

DNA concentrations were standardized to 10 ng/μL using PicoGreen(Molecular Probes) fluorescent dye. DNA pools, typically of 50 cases orcontrols, were made by mixing equal volumes of standardized DNA fromeach individual member of the pool. Each allele was amplified separatelyby PCR using 3 ng of pooled DNA. The allele frequency was calculatedfrom amplification curves for each allele. At least four independentpools of DNA were amplified in duplicate for each allele. Genotyping ofindividual DNA samples was similarly performed using 0.3 ng of DNA.

Ethics

Subjects of all three studies gave informed consent and completed anInstitutional Review Board approved questionnaire.

Statistical Methods

Association between MI status and allele frequencies was assessed bytwo-tailed χ² tests, and between MI status and genotype by logisticregression using an additive inheritance model (Wald test). In Study 2and Study 3, since a single prespecified risk allele was tested for eachSNP, one-sided P values and 90% confidence intervals are presented (forodds ratios greater than one, there is 95% confidence that the true riskestimate is greater than the lower bound of a 90% confidence interval).A P threshold value of 0.05 was used in all three studies, and adjustedfor multiple testing by calculating the false discovery rate (FDR) inStudy 3. FDR was calculated using the MULTTEST procedure (SASstatistical package Version 9.1); for SNPs that were in the same gene,only the SNP with the higher (less significant) P value was included inthe calculation.

Results

The allele frequencies of 17,576 putative functional SNPs were measuredin Study 1 cases and controls using pooled DNA samples, and 1,949 SNPswere identified that were associated with MI (P<0.05) and had minorallele frequency estimates that were greater than 1%. For these 1,949SNPs, allele frequencies in Study 2 cases and controls were determinedusing pooled DNA samples and it was verified that the risk alleleidentified in Study 1 was also associated with risk of MI in Study 2.For those SNPs that were associated with MI and had the same riskalleles in both pooling studies, the association of the SNP with MI inStudy 1 and Study 2 was then confirmed by genotyping individual DNAsamples. It was found that the risk alleles of 24 SNPs in 23 genes wereassociated with MI in both studies using an additive inheritance model(Table 12) and a P value threshold of 0.05. Next, the hypotheses thatthe risk alleles of these 24 SNPs would be associated with MI weretested in Study 3. It was found that the risk allele of 5 SNPs, in 4genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MIusing an additive inheritance model after adjustment for age and sex(Table 13) (false discovery rate=0.23). The distribution of thegenotypes for each of the SNPs did not deviate from what was expectedunder Hardy-Weinberg equilibrium (P>0.5). Further adjustment fortraditional risk factors (dyslipidemia, hypertension, smoking status,and BMI), did not appreciably change the risk estimate for the four SNPsLPA, FXN (2 SNPs), and HLA-DPB2 (Table 13; for the ENO1 SNP, afterfurther adjustment for traditional risk factors, OR=1.09, 90% CI0.85-1.38, P=0.28, and the ENO1 SNP trended toward association withdyslipidemia (P=0.1)).

Discussion

An analysis was conducted of 17,576 SNPs that could potentially affectgene function or expression in three case-control studies of MI, and 5SNPs were identified in four genes (ENO1, FXN (2 SNPs), HLA-DPB2, andLPA) that were associated with MI.

The first SNP is located in ENO1, a gene that encodes α-enolase, aglycolytic enzyme that catalyzes the conversion of 2-phospho-D-glycerateto phosphoenolpyruvate. α-enolase is also known to be a plasminogenreceptor on the surface of hematopoietic cells and endothelial cells[11]. Thus, α-enolase could contribute to fibrinolysis, hemostasis, andarterial thrombus formation—processes that are critical in thepathophysiology of MI. The SNP in ENO1 (rs1325920) is located about 1 kbupstream of the gene and could be involved in transcriptionalregulation.

Two of the SNPs are in the FXN gene. The FXN gene encodes Frataxin, amitochondrial protein involved in maintaining cellular iron homeostasis[12]. Expanded GAA triplet repeats in intron 1 of FXN leads to silencingof the FXN gene and to accumulation of iron in the mitochondria, whichmakes mitochondria sensitive to oxidative stress [13]. These changeslead to Friedreich's ataxia, an autosomal recessive disease of thecentral nervous system that is frequently associated hypertrophiccardiomyopathy [12]. The two SNPs in FXN found to be associated with MIare located in the 3′ untranslated region of FXN (rs 10890) and in aputative transcription factor binding site (rs3793456), thus one or bothof these SNPs could have an effect on FXN gene expression. These twoSNPs are in linkage disequilibrium (r²=0.57 in Study 1).

The fourth SNP (rs3798220 in LPA) encodes a methionine to isoleucinesubstitution at amino acid 4399 of apolipoprotein(a). It has beenpreviously shown that this SNP is associated with coronary arterynarrowing and with increased levels of plasma lipoprotein(a) incase-control studies [10]. This SNP was also associated with incidentmyocardial infarction in the Cardiovascular Health Study, apopulation-based prospective study of about 5000 individuals aged 65 orolder [14].

As described above, certain aspects of the invention relate to using SNPrs3798220 for utilities related to hormone replacement therapy (HRT).

The fifth SNP that is associated with MI in this study is in HLA-DPB2(rs35410698). HLA-DPB2 is a pseudogene in the Human Leukocyte Antigen(HLA) region [15].

REFERENCES

(Reference Numbers Correspond to Example 2 Only)

-   1 American Heart Association (2002) Heart disease and stroke    statistics: 2005 update. American Heart Association, Dallas-   2. Marenberg M E, Risch N, Berkman L F, Floderus B, de Faire    U (1994) Genetic susceptibility to death from coronary heart disease    in a study of twins. N Engl J Med 330:1041-1046-   3. Cohen J C, Boerwinkle E, Mosley T H Jr, Hobbs H H (2006) Sequence    variations in PCSK9, low LDL, and protection against coronary heart    disease. N Engl J Med 354:1264-1272.-   4. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt N P et    al. (2008) Polymorphisms associated with cholesterol and risk of    cardiovascular events. N Engl J Med 358:1240-1249.-   5. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R et    al. (2007) A common allele on chromosome 9 associated with coronary    heart disease. Science 316:1488-1491.-   6. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S,    Blondal T et al. (2007) A common variant on chromosome 9p21 affects    the risk of myocardial infarction. Science 316:1491-1493.-   7. Shiffman D, Rowland C M, Sninsky J J, Devlin J J (2006)    Polymorphisms associated with coronary heart disease: better by the    score. Curr Opin Mol Ther 8:493-499.-   8. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M et    al. (2005) Identification of four gene variants associated with    myocardial infarction. Am J Hum Genet 77:596-605.-   9. Shiffman D, Rowland C M, Louie J Z, Luke M M, Bare L A et    al. (2006) Gene Variants of VAMP8 and HNRPUL1 Are Associated With    Early-Onset Myocardial Infarction. Arterioscler Thromb Vasc Biol    26:1613-1618.-   10. Luke M M, Kane J P, Liu D M, Rowland C M, Shiffman D et    al. (2007) A polymorphism in the protease-like domain of    apolipoprotein(a) is associated with severe coronary artery disease.    Arterioscler Thromb Vasc Biol 27:2030-2036.-   11. Pancholi V. (2001) Multifunctional alpha-enolase: its role in    diseases. Cell Mol Life Sci 58:902-920.-   12. Gottesfeld J M (2007) Small molecules affecting transcription in    Friedreich ataxia. Pharmacol Ther 116:236-248.-   13. Al-Mandawi S, Pinto R M, Varshney D, Lawrence L, Lowrie M B et    al. (2006) Genomics 88:580-590.-   14. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z et    al. (2008) Association of Gene Variants With Incident Myocardial    Infarction in the Cardiovascular Health Study. Arterioscler Thromb    Vasc Biol 28:173-179.-   15. de Bakker P I, McVean G, Sabeti P C, Miretti M M, Green T et    al. (2006) A high-resolution HLA and SNP haplotype map for disease    association studies in the extended human MHC. Nat Genet    38:1166-1172.-   16. Topol E J, McCarthy J, Gabriel S, Moliterno D J, Rogers W J et    al. (2001) Single nucleotide polymorphisms in multiple novel    thrombospondin genes may be associated with familial premature    myocardial infarction. Circulation 104:2641-2644.

Example 3 Fine-Mapping SNPs Associated with CVD

SNPs surrounding GOSR2SNP rs197922 (hCV2275273)

As described above in Example 1, a SNP in GOSR2 (rs197922, hCV2275273)was identified as being associated with MI. In order to determine ifthere are other SNPs that are also associated with MI in the region ofchromosome 17 surrounding this GOSR2SNP, other SNPs in a 215 kb regionsurrounding rs197922 were genotyped and analyzed. This region of 215 kbincluded all the SNPs with r²>0.3 with rs197922 based on HapmapCaucasian population. SNPs in this region were interrogated usingtagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8were genotyped in samples from UCSF Study 1 (“UCSF1”) (793 MI cases and1000 controls). For SNPs that were in LD with rs197922 (r²>0.3), taggingSNPs with r²>0.90 were used. SNPs that were significantly associatedwith MI (I-sided p-value of <0.05) in UCSF1 are provided in Table 10.

SNPs Surrounding ENO1 SNP rs1325920 (hCV8824241)

As described above in Example 2, a SNP in ENO1 (rs1325920, hCV8824241)was identified as being associated with MI. In order to determine ifthere are other SNPs that are also associated with MI in the region ofchromosome 1 surrounding this ENO1 SNP, other SNPs in a 582 kb regionsurrounding rs1325920 were genotyped and analyzed. This region of 582 kbincluded all the SNPs with r²>0.3 with rs1325920 based on HapmapCaucasian population. SNPs in this region were interrogated usingtagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8were genotyped in samples from UCSF1 (762 MI cases and 857 controls).For SNPs that were in LD with rs1325920 (r²>0.3), tagging SNPs withr²>0.90 were used. Some of the SNPs that were associated with MI inUCSF1 were also genotyped in a second sample set, UCSF2 (579 MI casesand 1159 controls). SNPs that were significantly associated with MI(1-sided p-value of <0.05) in UCSF1 and were also associated with MI inUCSF2 (or were not tested in UCSF2) are provided in Table 14.

SNPs Surrounding FXN SNP rs10890 (hCV1463226)

As described above in Example 2, a SNP in FXN (rs10890, hCV1463226) wasidentified as being associated with MI. In order to determine if thereare other SNPs that are also associated with MI in the region ofchromosome 9 surrounding this FXN SNP, other SNPs in a 203 kb regionsurrounding rs10890 were genotyped and analyzed. This region of 203 kbincluded all the SNPs with r²>0.3 with rs10890 based on Hapmap Caucasianpopulation. SNPs in this region were interrogated using tagging SNPs.SNPs which tagged other SNPs in this region with r²>0.8 were genotypedin samples from UCSF1 (762 MI cases and 857 controls). For SNPs thatwere in LD with rs10890 (r²>0.3), tagging SNPs with r²>0.90 were used.Some of the SNPs that were associated with MI in UCSF1 were alsogenotyped in a second sample set, UCSF2 (579 MI cases and 1159controls). SNPs that were significantly associated with MI (1-sidedp-value of <0.05) in UCSF1 and were also associated with MI in UCSF2 (orwere not tested in UCSF2) are provided in Table 15.

SNPs Surrounding RERE SNP rs10779705 (hCV32055477)

As shown in Table 14 (SNPs surrounding ENO1), a SNP in RERE (rs10779705,hCV32055477) was been identified as being associated with MI. In orderto determine if there are other SNPs that are also associated with MI inthe region of chromosome 1 surrounding this RERE SNP, other SNPs in a596 kb region surrounding rs10779705 were genotyped and analyzed. Thisregion of 596 kb included all the SNPs with r²>0.3 with rs10779705 basedon Hapmap Caucasian population. SNPs in this region were interrogatedusing tagging SNPs. SNPs which tagged other SNPs in this region withr²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857controls). For SNPs that were in LD with rs10779705 (r²>0.3), taggingSNPs with r²>0.90 were used. SNPs that were significantly associatedwith MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 16.

SNPs Surrounding VAMP8 SNP rs1010 (hCV2091644)

A SNP in VAMP8 (rs1010, hCV2091644) has been identified as beingassociated with MI. In order to determine if there are other SNPs thatare also associated with MI in the region of chromosome 2 surroundingthis VAMP8 SNP, other SNPs in a 220 kb region surrounding rs1010 weregenotyped and analyzed. This region of 220 kb included all the SNPs withr²>0.3 with rs1010 based on Hapmap Caucasian population. SNPs in thisregion were interrogated using tagging SNPs. SNPs which tagged otherSNPs in this region with r²>0.8 were genotyped in samples from UCSF1(793 MI cases and 1000 controls). For SNPs that were in LD with rs1010(r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that weresignificantly associated with MI (1-sided p-value of <0.05) in UCSF1 areprovided in Table 17.

SNPs Surrounding LPA SNP rs3798220 (hCV25930271)

As described above in Example 2, a SNP in LPA (rs3798220, hCV25930271)was identified as being associated with MI. In order to determine ifthere are other SNPs that are also associated with MI in the region ofchromosome 6 surrounding this LPA SNP, other SNPs in a 442 kb regionsurrounding rs3798220 (between rs9355797 and rs1950562) were genotypedand analyzed. This region of 442 kb included all the SNPs with r²>0.2with rs3798220 based on Hapmap Caucasian population. SNPs in this regionwere interrogated using tagging SNPs. SNPs which tagged other SNPs inthis region with r²>0.8 were genotyped in samples from UCSF1 (762 MIcases and 857 controls). SNPs that were significantly associated with MI(1-sided p-value of <0.05) in UCSF1 are provided in Table 18.

In a further analysis of SNPs in this 442 kb region surroundingrs3798220, SNPs were analyzed for association with MI risk using ameta-analysis of two case-control studies of MI, the UCSF1 and USCF2studies. As indicated in the preceding paragraph, the UCSF1 studyincluded 762 MI cases and 857 controls. The UCSF2 study included 579 MIcases and 1159 controls. In both the UCSF1 and UCSF2 studies, cases hada confirmed history of MI and controls had no history of CHD. Ameta-analysis of the UCSF1 and UCSF2 studies was also used to analyzewhether these SNPs are also associated with Lp(a) levels (Lpa level wastransformed to Log 10Lpa). SNPs that were significantly associated(p-value of <0.1) with both MI risk and Lp(a) levels in themeta-analysis of the UCSF1 and UCSF2 studies are provided in Table 19.

Example 4 SNPs (From a Functional Genome Scan) Associated with CVD inTwo Studies

SNPs identified in a functional genome scan (FGS) were analyzed fortheir association with CVD, particularly MI. For these SNPs, geneticdata from two case-control studies of MI were analyzed withoutstratification. In one study, UCSF1, there were 762 cases and 857controls. In the second study, UCSF2, there were 579 cases and 1159controls. In both studies, cases had a confirmed history of MI andcontrols had no history of CHD. SNPs showing significant (p-value of<0.1) association with MI risk in both studies are provided in Table 20.

Example 5 SNPs Associated with Response to Statin Therapy and with Riskfor CVD in the CARE Study

The CARE (“Cholesterol and Recurrent Events”) study, which is arandomized multicentral double-blinded trial of secondary prevention ofMI with pravastatin (Pravachol®) in individuals who have previously hadan MI, is described in Sacks et al. (1991) Am. J. Cardiol. 68: 1436-1446and Sacks et al. (1996) New England Journal of Medicine 335: 1001-1009.The CARE trial, including an analysis of SNPs therein, is also describedin Iakoubova et al., “Association of the Trp719Arg polymorphism inkinesin-like protein 6 with myocardial infarction and coronary heartdisease in 2 prospective trials: the CARE and WOSCOPS trials”, J Am CollCardiol. 2008 Jan. 29; 51(4):435-43.

A well-documented MI was one of the enrollment criteria for entry intothe CARE study. Patients were enrolled in the CARE trial from 80participating study centers. Men and post-menopausal women were eligiblefor the trial if they had had an acute MI between 3 and 20 months priorto randomization, were 21 to 75 years of age, and had plasma totalcholesterol levels of less than 240 mg/deciliter, LDL cholesterol levelsof 115 to 174 mg/deciliter, fasting triglyceride levels of less than 350mg/deciliter, fasting glucose levels of no more than 220 mg/deciliter,left ventricular ejection fractions of no less than 25%, and nosymptomatic congestive heart failure. Patients were randomized toreceive either 40 mg of pravastatin once daily or a matching placebo.The primary endpoint of the CARE trial was death from a coronary eventor nonfatal MI and the median duration of follow-up was 5.0 years(range, 4.0 to 6.2 years). For the study of CARE described in thisExample and shown in Tables 21-22, two endpoints were investigated: theprimary endpoint of CARE (a composite endpoint of fatal coronary eventor nonfatal MI, and identified as “endpt1” in the Endpoint column ofTables 21-22) and a composite endpoint of confirmed fatal or nonfatal MI(identified as “rmi” in the Endpoint column of Tables 21-22).

Table 21 provides SNPs associated with reduction of CHD risk,particularly risk for MI and recurrent MI, by Pravastatin in the CAREstudy, and Table 22 provides SNPs associated with risk of CHD,particularly risk for MI and recurrent MI, in the placebo arm of theCARE study. The SNPs provided in Table 22 are a subset of the SNPsprovided in Table 21; thus, the SNPs provided in Table 22 are associatedwith both increased CHD risk as well as reduction of CHD risk by statintreatment (e.g., Pravastatin).

Specifically, Table 21 provides SNPs for which the effect of pravastatinon the primary endpoint of the CARE study (identified as “endpt1” in theEndpoint column) or the recurrent MI endpoint (identified as “rmi” inthe Endpoint column) was analyzed by genotype subgroups and for whichpravastatin reduced risk in one genotype subgroup but not in another(P-interaction between statin treatment and genotype for the enpdpoint<0.1).

Table 22 provides a subset of SNPs from Table 21 that were associated(p<0.1) with time to occurrence of first event, either the CARE primaryendpoint (“endpt1”) or recurrent MI endpoint (“rmi”), in the placebogroup of the CARE study. In Table 22, the HR (including lower and upperconfidence intervals) and p-values indicated for each SNP correspond toAllele 1 (Allele 2 is the reference allele, which is considered to haveHR=1).

HR stands for Hazard Ratio, which is a concept similar to Odds Ratio(OR). The HR in event-free survival analysis is the effect of anexplanatory variable on the hazard or risk of an event. For examples, HRdescribes the likelihood of developing MI based on comparison of rate ofcoronary events between carriers of a certain allele and noncarriers ofthe allele; therefore, HR=1.5 would mean that carriers of the allelehave 50% higher risk of coronary events during the study follow-up thannon-carriers. HR can also describe the effect of statin therapy oncoronary events based on comparison of the rate of coronary eventsbetween patients treated with statin and patients treated with placeboin subgroups defined by SNP genotype; therefore, HR=0.5 would mean that,for example, carriers of a certain allele had a 50% reduction ofcoronary events by statin therapy as compared to placebo. In Table 21,p-interaction values were calculated. An interaction (or effectmodification) is formed when a third variable modifies the relationbetween an exposure and outcome. A p-interaction <0.1 indicates that athird variable (genotype) modifies the relation between an exposure(statin treatment) and outcome (CARE primary endpoint or recurrent MI).Genotype and drug interaction is present when the effect of statins(incidence rate of disease in statin-treated group, as compared toplacebo) differs in patients with different genotypes.

Example 6 Calculated Linkage Disequilibrium (LD) SNPs Associated withCVD

Another investigation was conducted to identify additional SNPs that arecalculated to be in linkage disequilibrium (LD) with certain“interrogated SNPs” that have been found to be associated with CVD(particularly CHD, especially MI, or hypertension), as described hereinand shown in the tables. The interrogated SNPs are shown in column 1(which indicates the hCV identification numbers of each interrogatedSNP) and column 2 (which indicates the public rs identification numbersof each interrogated SNP) of Table 6. The methodology is describedearlier in the instant application. To summarize briefly, the powerthreshold (7) was set at an appropriate level, such as 51%, fordetecting disease association using LD markers. This power threshold isbased on equation (31) above, which incorporates allele frequency datafrom previous disease association studies, the predicted error rate fornot detecting truly disease-associated markers, and a significance levelof 0.05. Using this power calculation and the sample size, a thresholdlevel of LD, or r² value, was derived for each interrogated SNP (r_(T)², equations (32) and (33) above). The threshold value r_(T) ² is theminimum value of linkage disequilibrium between the interrogated SNP andits LD SNPs possible such that the non-interrogated SNP still retains apower greater or equal to T for detecting disease association.

Based on the above methodology, LD SNPs were found for the interrogatedSNPs. Several exemplary LD SNPs for the interrogated SNPs are listed inTable 6; each LD SNP is associated with its respective interrogated SNP.Also shown are the public SNP IDs (rs numbers) for the interrogated andLD SNPs, when available, and the threshold r² value and the power usedto determine this, and the r² value of linkage disequilibrium betweenthe interrogated SNP and its corresponding LD SNP. As an example inTable 6, the interrogated SNP rs2145270 (hCV10048483) was calculated tobe in LD with rs1000972 (hCV10048484) at an r² value of 0.9242, based ona 51% power calculation, thus establishing the latter SNP as a markerassociated with CVD as well.

In general, the threshold r_(T) ² value can be set such that one ofordinary skill in the art would consider that any two SNPs having an r²value greater than or equal to the threshold r_(T) ² value would be insufficient LD with each other such that either SNP is useful for thesame utilities, such as determining an individual's risk for CVD such asCHD (particularly MI) or hypertension. For example, in variousembodiments, the threshold r_(T) ² value used to classify SNPs as beingin sufficient LD with an interrogated SNP (such that these LD SNPs canbe used for the same utilities as the interrogated SNP, for example) canbe set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97,0.98, 0.99, 1, etc. (or any other r² value in-between these values).Threshold r_(T) ² values may be utilized with or without consideringpower or other calculations.

All publications and patents cited in this specification are hereinincorporated by reference in their entirety. Modifications andvariations of the described compositions, methods and systems of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments andcertain working examples, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the above-described modes for carryingout the invention that are obvious to those skilled in the field ofmolecular biology, genetics and related fields are intended to be withinthe scope of the following claims.

TABLE 5 Marker Alleles Primer 1 (Allele-Specific Primer)Primer 2 (Allele-Specific Primer) Common Primer hCV10048483 C/TACAGCGTTTGACACTTCG (SEQ ID NO: 4007)AACAGCGTTTGACACTTCA (SEQ ID NO: 4008) GAAACTAGGAGCAGAGGAGAGACTA (SEQ IDNO: 4009) hCV1026586 A/G GTCCAGCTTAATAATTAACTTGTCAAATT (SEQ IDTCCAGCTTAATAATTAACTTGTCAAATC (SEQ IDGCCATGAGCTCATTGCCTACAA (SEQ ID NO: 4012) NO: 4010) NO: 4011) hCV1030264A/G AGGTAGATATCGTGGCTAAGAT (SEQ ID NO: 4013)GGTAGATATCGTGGCTAAGAC (SEQ ID NO: 4014) CGTCTTCTCGGATGTCATAGTGC (SEQ IDNO: 4015) hCV1116794 A/G GTGAGTTCTCAGATGGTTGA (SEQ ID NO: 4016)TGAGTTCTCAGATGGTTGG (SEQ ID NO: 4017)GCTTCAAGCTGTTGACAGTG (SEQ ID NO: 4018) hCV11170747 A/GAATTTTTCATTCTGCATGTGTT (SEQ ID NO: 4019)AATTTTTCATTCTGCATGTGTC (SEQ ID NO: 4020)CCAGGGCTCTTTCAAGATAGTA (SEQ ID NO: 4021) hCV11181829 C/TGATGGAGTTTTGAGGAACC (SEQ ID NO: 4022)CGATGGAGTTTTGAGGAACT (SEQ ID NO: 4023)CCCTGGGCAGAATCAGA (SEQ ID NO: 4024) hCV11225994 A/GTCCCAATCCCAGGACA (SEQ ID NO: 4025) CCCAATCCCAGGACG (SEQ ID NO: 4026)TGACATTGCACTCTCAAATATTT (SEQ ID NO: 4027) hCV11231076 C/TAGTCATGGTGGACGGTG (SEQ ID NO: 4028) CAGTCATGGTGGACGGTA (SEQ ID NO: 4029)CTTGGTGCTGTCCTCACTGTAGTA (SEQ ID NO: 4030) hCV11276368 C/TCGCGGAGTGTCAAGAGG (SEQ ID NO: 4031) CGCGGAGTGTCAAGAGA (SEQ ID NO: 4032)ACCTTGGGCAAAAAATACAT (SEQ ID NO: 4033) hCV11315168 C/GGTTGTTTGCTTCATCTCTGC (SEQ ID NO: 4034)GTTGTTTGCTTCATCTCTGG (SEQ ID NO: 4035)AGTGCTGGGCTCAAGAAC (SEQ ID NO: 4036) hCV11315171 C/TATTTCTGAATAACTGAAGTTGGTC (SEQ ID NO: 4037)ATTTCTGAATAACTGAAGTTGGTT (SEQ ID NO: 4038)CCCTACCTGGGTTATCAGTAAT (SEQ ID NO: 4039) hCV11398434 C/TAATGAAATCTAGGAATAGTGACCAC (SEQ ID NO: 4040)CAATGAAATCTAGGAATAGTGACCAT (SEQ ID NO: 4041)CTTCAGCCCAAGAGTTTGAGACTA (SEQ ID NO: 4042) hCV11398437 C/TAGAGTATGTGTAATTAAGTCGCTAC (SEQ ID NO: 4043)AAGAGTATGTGTAATTAAGTCGCTAT (SEQ ID NO: 4044)ACTGAGGATGAGTAATTATGTCTTATTAGGACCAT AG (SEQ ID NO: 4045) hCV11433557 G/CTGATGAGTGTCGAAATGGAG (SEQ ID NO: 4046)TGATGAGTGTCGAAATGGAC (SEQ ID NO: 4047)ACCGGTTCTGCTTTGATAAC (SEQ ID NO: 4048) hCV11438723 C/TACGCGTGTCTTTCTCAC (SEQ ID NO: 4049) ACGCGTGTCTTTCTCAT (SEQ ID NO: 4050)AAGTTACTTAAAATCTGCTTTTTCTTAG (SEQ ID NO: 4051) hCV11446935 G/TGGCTGAAATTATTCCAATAAAGGAC (SEQ ID NO: 4052)GGCTGAAATTATTCCAATAAAGGAA (SEQ ID NO: 4053)ACCAGGCTGTTGACCTTGCTATAA (SEQ ID NO: 4054) hCV11461296 C/GGACTGAGGCCCACGC (SEQ ID NO: 4055) GACTGAGGCCCACGG (SEQ ID NO: 4056)GGGTCTGCAGGTTAACAACA (SEQ ID NO: 4057) hCV11466079 A/GCCCATACCCAAGGAACCTT (SEQ ID NO: 4058)CCCATACCCAAGGAACCTC (SEQ ID NO: 4059)GGATCAGCCAAGCCAGACTT (SEQ ID NO: 4060) hCV11466848 A/GCTGGACTTCTGGGTCCT (SEQ ID NO: 4061) TGGACTTCTGGGTCCC (SEQ ID NO: 4062)CAAGAAGCTGAGCGAGTGTCT (SEQ ID NO: 4063) hCV11504800 A/TTAACAATTTGGTTTATATCCTCCCT (SEQ ID NO: 4064)ACAATTTGGTTTATATCCTCCCA (SEQ ID NO: 4065)CAGCTCTACATAGTATCCTGGAGAGAC (SEQ ID NO: 4066) hCV11513719 C/TTCCTCCGGTGTCAGTTTAG (SEQ ID NO: 4067)TCCTCCGGTGTCAGTTTAA (SEQ ID NO: 4068)GCAGTGGCCAGGGTTCAT (SEQ ID NO: 4069) hCV11568668 A/GCTTTCACTCACTCAACACATACTTA (SEQ ID NO: 4070)TTCACTCACTCAACACATACTTG (SEQ ID NO: 4071)GCTCAGTTGGGAGATGTGTAGGTA (SEQ ID NO: 4072) hCV11592758 T/CCATCCAACAGCTCTTCTATCAT (SEQ ID NO: 4073)CATCCAACAGCTCTTCTATCAC (SEQ ID NO: 4074)CAAACATCCGAGGACAAG (SEQ ID NO: 4075) hCV11623551 C/TACTCTTTGATGGCAACCATG (SEQ ID NO: 4076)TTAACTCTTTGATGGCAACCATA (SEQ ID NO: 4077)GGTTTTAAGCCAGCACTCTTAGACT (SEQ ID NO: 4078) hCV11628130 T/ACTGCCCTCTTTTTAGCAGA (SEQ ID NO: 4079)CTGCCCTCTTTTTAGCAGT (SEQ ID NO: 4080)CCCTTTCTCATTCATTCATTTT (SEQ ID NO: 4081) hCV11642651 C/TAAGGATGGCCTCATCAG (SEQ ID NO: 4082) AAGGATGGCCTCATCAA (SEQ ID NO: 4083)CCAGGATGGAGATGAAGAGA (SEQ ID NO: 4084) hCV11678789 G/TCCACTGAAATGCTACTTTGAGTAAC (SEQ ID NO: 4085)CCACTGAAATGCTACTTTGAGTAAA (SEQ ID NO: 4086)AGACAATCTGAGACATGCGAAGACT (SEQ ID NO: 4087) hCV11688401 A/GCCCTTTCCCAGGCTTATT (SEQ ID NO: 4088)CCCTTTCCCAGGCTTATC (SEQ ID NO: 4089)CCTCAACCAGGAAGTCAGAG (SEQ ID NO: 4090) hCV11689916 A/TTGTGAGTGGGCCTTCACT (SEQ ID NO: 4091) GTGAGTGGGCCTTCACA (SEQ ID NO: 4092)GGAGCCCCGCTTCAT (SEQ ID NO: 4093) hCV11697322 A/GCAGTTCGTGCTATTGAGAAAAT (SEQ ID NO: 4094)CAGTTCGTGCTATTGAGAAAAC (SEQ ID NO: 4095)CAAAGAAAAACAGATCACACAGAT (SEQ ID NO: 4096) hCV11703905 C/TGCACAGAAAGCCGTGAG (SEQ ID NO: 4097) GCACAGAAAGCCGTGAA (SEQ ID NO: 4098)CTGTAAGCTCCTCTGGTTCAG (SEQ ID NO: 4099) hCV11761245 C/TACACACTTCACAATGGACG (SEQ ID NO: 4100)CACACACTTCACAATGGACA (SEQ ID NO: 4101)CAGTAAACCTGGCACTCTTCAGTAGT (SEQ ID NO: 4102) hCV11764545 G/TCGAAGCTTCCGAGGAAG (SEQ ID NO: 4103) CGAAGCTTCCGAGGAAT (SEQ ID NO: 4104)GACACCGGACGAGAGAGAC (SEQ ID NO: 4105) hCV11765753 A/GGAGAAAAAAGAACAGATGTCCTT (SEQ ID NO: 4106)GAGAAAAAAGAACAGATGTCCTC (SEQ ID NO: 4107)TGATGCCTCTCAGCATTTATAC (SEQ ID NO: 4108) hCV11846435 C/TGCTGGGAACCTCTATCCC (SEQ ID NO: 4109)GCTGGGAACCTCTATCCT (SEQ ID NO: 4110) GGGCTCATGAGGAAAGTTTATGTG (SEQ IDNO: 4111) hCV11854426 C/T CATAATGATGTTGGTAGGGTCG (SEQ ID NO: 4112)CATAATGATGTTGGTAGGGTCA (SEQ ID NO: 4113)CCAGATTGATTCATGCTCCTCTCAC (SEQ ID NO: 4114) hCV11856381 A/GCAATGGTGGGCATGTCTTAT (SEQ ID NO: 4115)AATGGTGGGCATGTCTTAC (SEQ ID NO: 4116) GAGGGCTAAAGGAAAGAGGTGTTCT (SEQ IDNO: 4117) hCV11864162 A/C CCCTTTGCCTTGTCGTT (SEQ ID NO: 4118)CCCTTTGCCTTGTCGTG (SEQ ID NO: 4119) CACTGCACCAGGCCTAGAAATAC (SEQ IDNO: 4120) hCV1188731 C/T GGCAGATAGTAGCTGTTCAATAAAC (SEQ ID NO: 4121)GGCAGATAGTAGCTGTTCAATAAAT (SEQ ID NO: 4122)TTTGGGTAGCAGATCACTTCATTAATCTGA (SEQ ID NO: 4123) hCV1188735 C/TCTTGCTCTGATAAGAACTTTACAAC (SEQ ID NO: 4124)CCTTGCTCTGATAAGAACTTTACAAT (SEQ ID NO: 4125)CTGCCGTGGCCTTTCAAAG (SEQ ID NO: 4126) hCV1188747 C/GTGAAAATGTTCCTGAGCTATGG (SEQ ID NO: 4127)TGAAAATGTTCCTGAGCTATGC (SEQ ID NO: 4128)ACTATCACCCAGAAGGCGATCATAC (SEQ ID NO: 4129) hCV11955747 A/CAAAGGGAAGGAGGTTACTTACT (SEQ ID NO: 4130)AGGGAAGGAGGTTACTTACG (SEQ ID NO: 4131)TCCTCTGTGGAGAGGGATAC (SEQ ID NO: 4132) hCV11960994 A/GTTTGTAAACACACAGAGATGATAAT (SEQ ID NO: 4133)TTTGTAAACACACAGAGATGATAAC (SEQ ID NO: 4134)TTTCCGCTCGACATGTAA (SEQ ID NO: 4135) hCV11972326 C/GTTCTTTTAAAGGATTGGTAAACTC (SEQ ID NO: 4136)TTCTTTTAAAGGATTGGTAAACTG (SEQ ID NO: 4137)AGAGCAGAACGAGGTTTTATTT (SEQ ID NO: 4138) hCV12020339 G/TGGACCCCCGAAGGC (SEQ ID NO: 4139) TGGACCCCCGAAGGA (SEQ ID NO: 4140)GGCCCCAACAGTTGACTG (SEQ ID NO: 4141) hCV12022345 A/TAGTGGCCTCATCCTCCT (SEQ ID NO: 4142) GTGGCCTCATCCTCCA (SEQ ID NO: 4143)GAACGCTTACGAGCCTTATC (SEQ ID NO: 4144) hCV12034662 A/GGGGGCTATGTAGACTACATCTTTA (SEQ ID NO: 4145)GGGCTATGTAGACTACATCTTTG (SEQ ID NO: 4146)TTCAACAATGCGTTGGCAAGAGAT (SEQ ID NO: 4147) hCV12107274 C/TTGATGCTAATCTGTTCTCTGTG (SEQ ID NO: 4148)TCTGATGCTAATCTGTTCTCTGTA (SEQ ID NO: 4149)ATAACAAGAGGAAGGAGATCAGA (SEQ ID NO: 4150) hCV12108469 A/GTCGTGTCTACCTTAGGGTACA (SEQ ID NO: 4151)CGTGTCTACCTTAGGGTACG (SEQ ID NO: 4152)CGTATGGCTTCAGGATGTC (SEQ ID NO: 4153) hCV1239369 A/CGAAGATGTTACTCCTAATATCATACAGT (SEQ IDAAGATGTTACTCCTAATATCATACAGG (SEQ ID NO: 4155)GTTGTACCCTCATTGTGACATTAGGT (SEQ ID NO: 4154) NO: 4156) hCV1243283 A/GTTATTCCTAGTTCCAATGAAAGAT (SEQ ID NO: 4157)TTATTCCTAGTTCCAATGAAAGAC (SEQ ID NO: 4158)GCCTCTTGGGAGTACTCACTT (SEQ ID NO: 4159) hCV1253630 A/GTCGCAGGTGTCCCTA (SEQ ID NO: 4160) CGCAGGTGTCCCTG (SEQ ID NO: 4161)CCCCATCCCTTCTCA (SEQ ID NO: 4162) hCV1323634 C/TGAAGTGAAATAATGGTTCAGCATAC (SEQ ID NO: 4163)GAAGTGAAATAATGGTTCAGCATAT (SEQ ID NO: 4164)CTGCATCTGTTGAGATTATTGTATGACGTT (SEQ ID NO: 4165) hCV1323669 A/GGTGTTATACTGTATCACTCTTCTTTTCTAA (SEQ IDTGTTATACTGTATCACTCTTCTTTTCTAG (SEQ IDGGGGGCGGAACTTAGACA (SEQ ID NO: 4168) NO: 4166) NO: 4167) hCV1345898 C/TCAGTTTTCCATGGGTTCTACTAC (SEQ ID NO: 4169)CAGTTTTCCATGGGTTCTACTAT (SEQ ID NO: 4170)TTATGAAATGGTACAGACAAGTGAT (SEQ ID NO: 4171) hCV1361979 A/GCCAGTTTTGGTGTCAACTAGAAA (SEQ ID NO: 4172)CCAGTTTTGGTGTCAACTAGAAG (SEQ ID NO: 4173)TTGCAACCTGAAAAACATAACTA (SEQ ID NO: 4174) hCV1366867 A/GGGAGCCAGGCCTACAT (SEQ ID NO: 4175) GGAGCCAGGCCTACAC (SEQ ID NO: 4176)CGCCTCGACGAGATTCT (SEQ ID NO: 4177) hCV1375141 C/TCCTTCGGAGTTGCACAG (SEQ ID NO: 4178) CCTTCGGAGTTGCACAA (SEQ ID NO: 4179)TTTTTGGTGGGTTTCTCTGTA (SEQ ID NO: 4180) hCV1415464 C/GCCCTGGGGGTCTTTC (SEQ ID NO: 4181) CCCTGGGGGTCTTTG (SEQ ID NO: 4182)CCGTGGCCTCTGTGATT (SEQ ID NO: 4183) hCV1449414 T/CACACACATATGGTGGTTCATAAT (SEQ ID NO: 4184)CACACATATGGTGGTTCATAAC (SEQ ID NO: 4185)CATGTCCCAGCTCTTCTTG (SEQ ID NO: 4186) hCV1449416 T/ATATGCAAGGTGTTGTTATAGATTT (SEQ ID NO: 4187)GTATGCAAGGTGTTGTTATAGATTA (SEQ ID NO: 4188)GCGTTGTAACTGAGTTCATTATTC (SEQ ID NO: 4189) hCV1463112 C/TTTCAAGCTATTTGTAGTTCCTAGAG (SEQ ID NO: 4190)CTTCAAGCTATTTGTAGTTCCTAGAA (SEQ ID NO: 4191)GGTGTGGCCTTCTTTGGAAGATC (SEQ ID NO: 4192) hCV1463184 C/TGGTTAAATGACACTCTTTGGGG (SEQ ID NO: 4193)GGTTAAATGACACTCTTTGGGA (SEQ ID NO: 4194)GTTTCAGAAAGATTTGTCAGGACCACT (SEQ ID NO: 4195) hCV1463222 C/TTGTTTCTCCCACATATTCACATAC (SEQ ID NO: 4196)CTGTTTCTCCCACATATTCACATAT (SEQ ID NO: 4197)CGCTACATCACTCAGCTCATGAAA (SEQ ID NO: 4198) hCV1463224 C/TCAACTCACACGGGAAGAC (SEQ ID NO: 4199)CAACTCACACGGGAAGAT (SEQ ID NO: 4200) GTGAATATGTGGGAGAAACAGCACTAG (SEQ IDNO: 4201) hCV1463226 C/T ATTTCCTCCCTCACATGATAC (SEQ ID NO: 4202)ATTTCCTCCCTCACATGATAT (SEQ ID NO: 4203) TCAAAGAATGAAGAGTGAAGACA (SEQ IDNO: 4204) hCV1488444 G/T TCAACAGAATGCCATGAGC (SEQ ID NO: 4205)GTCAACAGAATGCCATGAGA (SEQ ID NO: 4206) CAAGGCAGAAGTAGTTGTCCAACAG (SEQ IDNO: 4207) hCV1489995 C/G GAGGCGAAAGGAACAGAG (SEQ ID NO: 4208)GAGGCGAAAGGAACAGAC (SEQ ID NO: 4209)GCGTGCTGAGGAGTAATGTAC (SEQ ID NO: 4210) hCV1550877 C/TGGTCCAAATAGACTAACTTTAAGTGAC (SEQ IDGGTCCAAATAGACTAACTTTAAGTGAT (SEQ ID NO: 4212)CCCACACAACATACAATTTACAAATGC (SEQ ID NO: 4211) NO: 4213) hCV1552894 A/GCAGATTCAGCCTCCCAA (SEQ ID NO: 4214) CAGATTCAGCCTCCCAG (SEQ ID NO: 4215)GCAGTTGGAAATCTGAATTTC (SEQ ID NO: 4216) hCV1552900 A/GGGGATGGAAGAGCTTCA (SEQ ID NO: 4217) GGGATGGAAGAGCTTCG (SEQ ID NO: 4218)CTGCAGCCTTCCTCTGAC (SEQ ID NO: 4219) hCV15746640 A/GGAAACGGCTGGTTTGTGT (SEQ ID NO: 4220) AACGGCTGGTTTGTGC (SEQ ID NO: 4221)TCCAATCTACCTTTTCCTTGTATT (SEQ ID NO: 4222) hCV15752705 C/GGCCTCCCCTGCTGC (SEQ ID NO: 4223) GGCCTCCCCTGCTGG (SEQ ID NO: 4224)AGGTCCCTTCTGCTGTAATG (SEQ ID NO: 4225) hCV15752716 C/TACGCTGCTGTTCCG (SEQ ID NO: 4226) CACGCTGCTGTTCCA (SEQ ID NO: 4227)CAGACAGACAACAATTCAGAAGAA (SEQ ID NO: 4228) hCV15758290 G/AGTCACACACCCAGGAGC (SEQ ID NO: 4229) GGTCACACACCCAGGAGT (SEQ ID NO: 4230)GGATGATTGCCATAATGAGTC (SEQ ID NO: 4231) hCV15760070 A/TTGTCCAGATCCACATAGAACA (SEQ ID NO: 4232)TTGTCCAGATCCACATAGAACT (SEQ ID NO: 4233)CTTTATGCAGCGGACCAT (SEQ ID NO: 4234) hCV15770510 C/TACGGCATCTTCTATCCG (SEQ ID NO: 4235) CACGGCATCTTCTATCCA (SEQ ID NO: 4236)CCAGCTGGTGGTGAGTG (SEQ ID NO: 4237) hCV15851335 C/TGATGGCATGGATGGC (SEQ ID NO: 4238) GGATGGCATGGATGGT (SEQ ID NO: 4239)GCAGGATGTGCTGTGATTAT (SEQ ID NO: 4240) hCV15851779 A/GCAACCTGACATGGAAGAAAT (SEQ ID NO: 4241)CAACCTGACATGGAAGAAAC (SEQ ID NO: 4242)GATGTGGTGGGATTTGACAT (SEQ ID NO: 4243) hCV15870728 C/TGAGAGAGAACAGCCAGAC (SEQ ID NO: 4244)GAGAGAGAACAGCCAGAT (SEQ ID NO: 4245)GCATCCCAGGTCAAGGTA (SEQ ID NO: 4246) hCV15871150 A/GCCCAAATTCTGCATAGCATAA (SEQ ID NO: 4247)CCCAAATTCTGCATAGCATAG (SEQ ID NO: 4248)GTGGGCTCGGGTCTCTA (SEQ ID NO: 4249) hCV15874689 A/GTGGAAAGCCTCAAGTCT (SEQ ID NO: 4250) GGAAAGCCTCAAGTCC (SEQ ID NO: 4251)TTCTAGAGGTGGTCAGCTAATACTT (SEQ ID NO: 4252) hCV15876011 T/GACCATCAGTTACCTTCATGACT (SEQ ID NO: 4253)CATCAGTTACCTTCATGACG (SEQ ID NO: 4254)GCGGACCACCTGTTAATC (SEQ ID NO: 4255) hCV15882274 G/ACATGGAGATCCAAGTCG (SEQ ID NO: 4256) ACATGGAGATCCAAGTCA (SEQ ID NO: 4257)GACTCAGGCAGGACAACC (SEQ ID NO: 4258) hCV15885004 A/GCTCCCCTACTCTGCTCATATAT (SEQ ID NO: 4259)CTCCCCTACTCTGCTCATATAC (SEQ ID NO: 4260) CATTCTCCCCACCAGGCATTTAT (SEQ IDNO: 4261) hCV15892430 C/T ACTGAGAGCTTGTCCTCAG (SEQ ID NO: 4262)ACTGAGAGCTTGTCCTCAA (SEQ ID NO: 4263)CACACCCAGAGACCACAGG (SEQ ID NO: 4264) hCV15954277 A/GTGTCGGTAAACATGGCA (SEQ ID NO: 4265) GTCGGTAAACATGGCG (SEQ ID NO: 4266)GGTGGGTGGTCTGACTCTC (SEQ ID NO: 4267) hCV15954645 A/TCTGATGGTATTTTACAGTGGATCA (SEQ ID NO: 4268)CTGATGGTATTTTACAGTGGATCT (SEQ ID NO: 4269)AAGACGCAACGAGCTTTGTGT (SEQ ID NO: 4270) hCV15955388 C/TTGCATTACTCGGACCC (SEQ ID NO: 4271) CTGCATTACTCGGACCT (SEQ ID NO: 4272)TGCCCGCACCTTGTC (SEQ ID NO: 4273) hCV15963535 C/GGTTGCTCATAGTTGCTGGC (SEQ ID NO: 4274)GTTGCTCATAGTTGCTGGG (SEQ ID NO: 4275)CAGCATCTTCGACAGAGACA (SEQ ID NO: 4276) hCV15963962 A/GTACTGTCCCGTGTTCCA (SEQ ID NO: 4277) CTGTCCCGTGTTCCG (SEQ ID NO: 4278)CTCTCCCAGAGCCCTCTAG (SEQ ID NO: 4279) hCV15963994 G/TGCTGCGTTTCTACTCTGC (SEQ ID NO: 4280)TGCTGCGTTTCTACTCTGA (SEQ ID NO: 4281) ACTCATGCGCATGCACATAAACA (SEQ IDNO: 4282) hCV15965796 C/G CGCCCTGCACTTTCAC (SEQ ID NO: 4283)CGCCCTGCACTTTCAG (SEQ ID NO: 4284)CCGTGCTCTACTGCTTCTCTA (SEQ ID NO: 4285) hCV15967490 C/TTGGAGGGTCCAACTCATAAC (SEQ ID NO: 4286)TGGAGGGTCCAACTCATAAT (SEQ ID NO: 4287) GGGATTGCTCAGCATCTCCTTAAAT (SEQ IDNO: 4288) hCV15973230 A/G TCACTGATGTCAATGAACACT (SEQ ID NO: 4289)ACTGATGTCAATGAACACC (SEQ ID NO: 4290)CCCATCCCAGAGTTCTTGTC (SEQ ID NO: 4291) hCV1600754 C/TATTTCCCTGGGAAGACTTC (SEQ ID NO: 4292)ATTTCCCTGGGAAGACTTT (SEQ ID NO: 4293) CTAGTGGTGGAAGGAAATGTTA (SEQ IDNO: 4294) hCV1603697 C/T CGGCCTGCGTGGAC (SEQ ID NO: 4295)CGGCCTGCGTGGAT (SEQ ID NO: 4296) GCCCAGGGCGTGTTCT (SEQ ID NO: 4297)hCV16044337 A/G TCCGGGTGCACGTATA (SEQ ID NO: 4298)CGGGTGCACGTATG (SEQ ID NO: 4299)TGGAGAGTGTTTGCTCATCTAC (SEQ ID NO: 4300) hCV16047108 A/GTGTTTTCATCCACTTGAACTGT (SEQ ID NO: 4301)TTTTCATCCACTTGAACTGC (SEQ ID NO: 4302)CAATTTTGGCTCCCTTAAAAG (SEQ ID NO: 4303) hCV16065831 C/TCTCCTGACTGTGAACAACTTATC (SEQ ID NO: 4304)CTCCTGACTGTGAACAACTTATT (SEQ ID NO: 4305)CCCCCAGTTGTGCATACAC (SEQ ID NO: 4306) hCV16140621 A/TAGCTGAAAGGAGAAGTCAGT (SEQ ID NO: 4307)AGCTGAAAGGAGAAGTCAGA (SEQ ID NO: 4308) CCCTGCTACGAAGGTGGAATATCT (SEQ IDNO: 4309) hCV16172339 A/T CTGCGGCTCCACCT (SEQ ID NO: 4310)TGCGGCTCCACCA (SEQ ID NO: 4311) TGGCATCTGCCATACTCA (SEQ ID NO: 4312)hCV16173091 T/C CACAGACTTGATGTTTTTGAAAGT (SEQ ID NO: 4313)CAGACTTGATGTTTTTGAAAGC (SEQ ID NO: 4314)TGCAAAGGAAGCAACTTCA (SEQ ID NO: 4315) hCV16179493 C/TGGGTCCGGCCACAC (SEQ ID NO: 4316) GGGTCCGGCCACAT (SEQ ID NO: 4317)GGGCCCCTCAGTGAAG (SEQ ID NO: 4318) hCV16179599 C/TCTGCTCTCAGAACCTCAGTC (SEQ ID NO: 4319)CTGCTCTCAGAACCTCAGTT (SEQ ID NO: 4320)CACTGCAGGGAAATAGAGAAA (SEQ ID NO: 4321) hCV16179628 A/GCAGGTTCACTGTTTCTCCAAT (SEQ ID NO: 4322)CAGGTTCACTGTTTCTCCAAC (SEQ ID NO: 4323)GAGCACATCCTTCCATTGTAA (SEQ ID NO: 4324) hCV16182835 A/GTGTTCTTCCTTATGATGATGT (SEQ ID NO: 4325)GTTCTTCCTTATGATGATGC (SEQ ID NO: 4326)GGCGTTCCTCTCACCTTAATA (SEQ ID NO: 4327) hCV16186452 C/TGGCACCCCCGACAG (SEQ ID NO: 4328) GGCACCCCCGACAA (SEQ ID NO: 4329)TCCTTATGCTCTCAGTGAAGTTC (SEQ ID NO: 4330) hCV16189421 C/TGCCATCATTTGCTTCTAACAC (SEQ ID NO: 4331)GCCATCATTTGCTTCTAACAT (SEQ ID NO: 4332)GCTTATTTGCCAGAAAACATTT (SEQ ID NO: 4333) hCV16192174 G/AGAGCACCTTAACTATAGATGGTG (SEQ ID NO: 4334)TGAGCACCTTAACTATAGATGGTA (SEQ ID NO: 4335)CTTGTCAAGGCACAGAATAATT (SEQ ID NO: 4336) hCV16196618 C/GATTAGCCCCAAAGCGTAC (SEQ ID NO: 4337)ATTAGCCCCAAAGCGTAG (SEQ ID NO: 4338) GCTTTAGAAGGCTGGATATTTATG (SEQ IDNO: 4339) hCV1639938 A/C AGTGGAGCTTCAGGGCT (SEQ ID NO: 4340)TGGAGCTTCAGGGCG (SEQ ID NO: 4341) CAGTGGAGACAGAGGATGTTTAC (SEQ IDNO: 4342) hCV1643239 C/T CCAGAGTCCACAGAAAGTTTC (SEQ ID NO: 4343)CCAGAGTCCACAGAAAGTTTT (SEQ ID NO: 4344)GAAAATAACGCAAGCAGTTTC (SEQ ID NO: 4345) hCV1647371 C/TCTGGCTGGGTCACTAACC (SEQ ID NO: 4346)GCTGGCTGGGTCACTAACT (SEQ ID NO: 4347)CCTCACCTGCATTCACATTT (SEQ ID NO: 4348) hCV1682755 C/TTGTTCTCAATGAATCAAAGCTATTAC (SEQ ID NO: 4349)CATGTTCTCAATGAATCAAAGCTATTAT (SEQ ID GTCTTCCCCATGTTCATACTCTTGT (SEQ IDNO: 4350) NO: 4351) hCV1690777 A/GGGCTTTACAGAAGGAAATGCT (SEQ ID NO: 4352)GCTTTACAGAAGGAAATGCC (SEQ ID NO: 4353)GCATGCGCTGAATTTTATATAG (SEQ ID NO: 4354) hCV1729928 A/GGGAAATTGTTGAGTGTTTGTAAAGT (SEQ ID NO: 4355)GGAAATTGTTGAGTGTTTGTAAAGC (SEQ ID NO: 4356)CAATGCCCAAAGTTGGCTATGATT (SEQ ID NO: 4357) hCV1741111 C/TCCTCAGAATGGCCAAAAAC (SEQ ID NO: 4358)CCTCAGAATGGCCAAAAAT (SEQ ID NO: 4359)CCAGGCAGCCAGACTTCT (SEQ ID NO: 4360) hCV1770462 A/GGCACCTCTGGGTGAAGAATA (SEQ ID NO: 4361)CACCTCTGGGTGAAGAATG (SEQ ID NO: 4362)GGCACAGGCAAGTCTGATT (SEQ ID NO: 4363) hCV1782711 C/TCCACTGCTGCAAGGAGTC (SEQ ID NO: 4364)CCACTGCTGCAAGGAGTT (SEQ ID NO: 4365) GCAGTCATCATATGGACAACTTAC (SEQ IDNO: 4366) hCV1801149 A/G GAGAGTCGCAGGGTATTTTAA (SEQ ID NO: 4367)GAGAGTCGCAGGGTATTTTAG (SEQ ID NO: 4368)AAAGGCCCAGGCTCTAGA (SEQ ID NO: 4369) hCV1802755 C/TCTCCTTAAGAAGAATGCCACC (SEQ ID NO: 4370)TCTCCTTAAGAAGAATGCCACT (SEQ ID NO: 4371)AGCCAGTTTAGCATTTACTCTTTACAAG (SEQ ID NO: 4372) hCV1843175 A/CCCCCGAAGCCTATGGCT (SEQ ID NO: 4373) CCCGAAGCCTATGGCG (SEQ ID NO: 4374)CGTCAGCACCCAACTCTG (SEQ ID NO: 4375) hCV1844077 A/GCCCTAAATGCAGAAATTGAATCTT (SEQ ID NO: 4376)CCCTAAATGCAGAAATTGAATCTC (SEQ ID NO: 4377)CCCTCTGAAATGCTGCTGTAACT (SEQ ID NO: 4378) hCV1948599 A/CGCAGTTTGAGTATAAATTGTTTGACTA (SEQ IDGCAGTTTGAGTATAAATTGTTTGACTC (SEQ ID NO: 4380)CAGTGACAGATGAGTGCAGAGAAT (SEQ ID NO: 4379) NO: 4381) hCV2002654 C/GGGAGCCCCAGGAAAG (SEQ ID NO: 4382) GGAGCCCCAGGAAAC (SEQ ID NO: 4383)AGAGCCCTCGGTTCTTG (SEQ ID NO: 4384) hCV2038 G/ACACGGCGGTCATGTG (SEQ ID NO: 4385) CCACGGCGGTCATGTA (SEQ ID NO: 4386)GGTGGAGCTTGGTTTCTCA (SEQ ID NO: 4387) hCV207123 C/GTGTAGATCATGTGGATGGATTG (SEQ ID NO: 4388)AATGTAGATCATGTGGATGGATTC (SEQ ID NO: 4389)CTGTCAGGCTGTCTGTAAGTCTCTAT (SEQ ID NO: 4390) hCV2091644 C/TTTCTGGGGCATACAACG (SEQ ID NO: 4391) CTTCTGGGGCATACAACA (SEQ ID NO: 4392)AGGGACAACCCTCCATAAA (SEQ ID NO: 4393) hCV2091649 A/GCCTCAGAGTATGTGCCCA (SEQ ID NO: 4394)CCTCAGAGTATGTGCCCG (SEQ ID NO: 4395)GCCCGGCTGCATCTAGTT (SEQ ID NO: 4396) hCV2091650 C/TTCTCTGAGCTGAGTGCC (SEQ ID NO: 4397) GTCTCTGAGCTGAGTGCT (SEQ ID NO: 4398)TCCCTATCCTAACTCTCCTTGTCT (SEQ ID NO: 4399) hCV2091669 A/TGTCAGTAGCGCTCACTTTT (SEQ ID NO: 4400)GTCAGTAGCGCTCACTTTA (SEQ ID NO: 4401) GGCTACTTAGCTGCAGTTCAAACTC (SEQ IDNO: 4402) hCV2091674 G/T CCACTTAATAACAACACTACTTGC (SEQ ID NO: 4403)GCCACTTAATAACAACACTACTTGA (SEQ ID NO: 4404)GACTGAGCCTGTTTCCTCACCTATAA (SEQ ID NO: 4405) hCV2143205 A/GTGTCGAATGGGAGTCTTCTT (SEQ ID NO: 4406)TGTCGAATGGGAGTCTTCTC (SEQ ID NO: 4407) CCTAGTAGTACAACGGAAGAAACAG (SEQ IDNO: 4408) hCV2146578 C/T CCTCCTAGAGAAGATCTGCAC (SEQ ID NO: 4409)CCTCCTAGAGAAGATCTGCAT (SEQ ID NO: 4410)AAGGCCCCTCTTCTGTCT (SEQ ID NO: 4411) hCV2146579 A/CTTCCTAACAGAGGCTTGGA (SEQ ID NO: 4412)TCCTAACAGAGGCTTGGC (SEQ ID NO: 4413)TGCAGTGTCCCCTAGAATG (SEQ ID NO: 4414) hCV2192261 C/TCCTACCTTGAATTCACCTATCTG (SEQ ID NO: 4415)CCTACCTTGAATTCACCTATCTA (SEQ ID NO: 4416)CATTTCCAAATCAGAAACATGA (SEQ ID NO: 4417) hCV2195496 C/TGCACCTCACAAACACCG (SEQ ID NO: 4418) TGCACCTCACAAACACCA (SEQ ID NO: 4419)GCCTCTTCTGCAAATGGATGATATACAC (SEQ ID NO: 4420) hCV2221541 C/TCCTGGAGTGGATGCCTTC (SEQ ID NO: 4421)CCTGGAGTGGATGCCTTT (SEQ ID NO: 4422)GGACAGCAGACACCTGAGC (SEQ ID NO: 4423) hCV22271999 C/TGAGCACCTTAACTATAGATGGTG (SEQ ID NO: 4424)TGAGCACCTTAACTATAGATGGTA (SEQ ID NO: 4425)CTTGTCAAGGCACAGAATAATT (SEQ ID NO: 4426) hCV22273354 A/GCAGGTCAGGCACAAACAT (SEQ ID NO: 4427)CAGGTCAGGCACAAACAC (SEQ ID NO: 4428) GAAGATGACCTGTTGAGTCAGTA (SEQ IDNO: 4429) hCV22274594 G/A ACAACAGGAGCACACCG (SEQ ID NO: 4430)GACAACAGGAGCACACCA (SEQ ID NO: 4431)GATGCAGTCCCTTTTTCTAAA (SEQ ID NO: 4432) hCV22274679 C/TTATCGCTGGGTAAACCG (SEQ ID NO: 4433) GTATCGCTGGGTAAACCA (SEQ ID NO: 4434)CGACTCTGAGGAGATGGAGTAT (SEQ ID NO: 4435) hCV22274761 A/GACTCCCCCAAGATCTTCT (SEQ ID NO: 4436) CCCCCAAGATCTTCC (SEQ ID NO: 4437)GCTCCCCCGACAAACT (SEQ ID NO: 4438) hCV22275550 C/TCCATCTGTTCCGCCG (SEQ ID NO: 4439) TCCATCTGTTCCGCCA (SEQ ID NO: 4440)TTACCCAGCAGCGAAGAC (SEQ ID NO: 4441) hCV22303 A/GAGCTTGGTTGTAGCCCA (SEQ ID NO: 4442) GCTTGGTTGTAGCCCG (SEQ ID NO: 4443)AGGCCAGCCTCCAAATCTTTC (SEQ ID NO: 4444) hCV2230606 A/GAAATGTTGTCAACGTCCA (SEQ ID NO: 4445) AATGTTGTCAACGTCCG (SEQ ID NO: 4446)AGTCACTGGCAGCAATGAT (SEQ ID NO: 4447) hCV2275263 A/TGTCCATCAGCAAATTGTCTCT (SEQ ID NO: 4448)GTCCATCAGCAAATTGTCTCA (SEQ ID NO: 4449) CCGATGACCTGGGGACATATTAG (SEQ IDNO: 4450) hCV2275272 C/T CCTTTCCTTGTCTGTCTGC (SEQ ID NO: 4451)CCTTTCCTTGTCTGTCTGT (SEQ ID NO: 4452)GAAGGAGGGGGAGGAATGACT (SEQ ID NO: 4453) hCV2275273 A/GAGAGGTCAGCACTTACAGTT (SEQ ID NO: 4454)AGAGGTCAGCACTTACAGTC (SEQ ID NO: 4455)CAAGCAAGCATAGACCAGATAT (SEQ ID NO: 4456) hCV2275276 A/GCCATTCACATACAAATCTTTCTTACT (SEQ IDCCATTCACATACAAATCTTTCTTACC (SEQ ID NO: 4458)CCAGATGAAACTTCTTCCTGGTCATT (SEQ ID NO: 4457) NO: 4459) hCV2276802 A/CTGGCTCAAGACCAAT (SEQ ID NO: 4460) TGGCTCAAGACCAAG (SEQ ID NO: 4461)CCCACATCCTTGCTGATC (SEQ ID NO: 4462) hCV2310409 A/TCTCAGGGAGGGAGAGAGA (SEQ ID NO: 4463)CTCAGGGAGGGAGAGAGT (SEQ ID NO: 4464)ACAGCTCAGGCAGAAACTG (SEQ ID NO: 4465) hCV2335281 G/TCAGCCTAGGCAGCATTG (SEQ ID NO: 4466) CAGCCTAGGCAGCATTT (SEQ ID NO: 4467)CCTGGGTTCAACCTTCTGAGTAGAT (SEQ ID NO: 4468) hCV2485037 A/GTGCAAGAGGACTAAGCATGA (SEQ ID NO: 4469)GCAAGAGGACTAAGCATGG (SEQ ID NO: 4470) GCGGCCTTGCACTCA (SEQ ID NO: 4471)hCV2503034 A/C ACGACAGGATCCTGAATGA (SEQ ID NO: 4472)CGACAGGATCCTGAATGC (SEQ ID NO: 4473)CCTAGCTCGTACCCACCTCT (SEQ ID NO: 4474) hCV2531086 A/GGCCCCCCTCTCTGAAGA (SEQ ID NO: 4475) CCCCCCTCTCTGAAGG (SEQ ID NO: 4476)CCAGTTCGTGGTATGTTCATCT (SEQ ID NO: 4477) hCV2531730 T/ACATTTGGCTATTTTTAGCTCTAAA (SEQ ID NO: 4478)ACATTTGGCTATTTTTAGCTCTAAT (SEQ ID NO: 4479)GCGGCTGGGTTTCTGT (SEQ ID NO: 4480) hCV2536595 A/GCATCCCGCGCCAT (SEQ ID NO: 4481) CATCCCGCGCCAC (SEQ ID NO: 4482)CCTCCAGAGAAGAAGAAGACAC (SEQ ID NO: 4483) hCV25472345 C/TGGTCACAGCCAGGC (SEQ ID NO: 4484) AGGTCACAGCCAGGT (SEQ ID NO: 4485)CCCCAGGAATATGTAAGTTGA (SEQ ID NO: 4486) hCV25472673 C/TTGGGCTCCATCCCAC (SEQ ID NO: 4487) TGGGCTCCATCCCAT (SEQ ID NO: 4488)CCAATTCTTTTTCTTCTTTCAGTT (SEQ ID NO: 4489) hCV25473098 A/GCACAGACTTGATGTTTTTGAAAGT (SEQ ID NO: 4490)CAGACTTGATGTTTTTGAAAGC (SEQ ID NO: 4491)TGCAAAGGAAGCAACTTCA (SEQ ID NO: 4492) hCV25474101 C/TGCTGCTATTTTTGTTATTATTATTTTCTAC (SEQ IDGCTGCTATTTTTGTTATTATTATTTTCTAT (SEQ IDGGCCTTACCATCTCCAGAAA (SEQ ID NO: 4495) NO: 4493) NO: 4494) hCV2553030C/T CCGGCTTGCACTTCAC (SEQ ID NO: 4496)CCGGCTTGCACTTCAT (SEQ ID NO: 4497) CTTTGTGGCCGCAGTAGT (SEQ ID NO: 4498)hCV2554615 C/G GCTCAGTCATTACCTTTGCC (SEQ ID NO: 4499)GCTCAGTCATTACCTTTGCG (SEQ ID NO: 4500) ACTGCTCCCTCCCATTCATACAG (SEQ IDNO: 4501) hCV2554721 A/G TTAATTCTTTTGGCACAGGTAGA (SEQ ID NO: 4502)ATTCTTTTGGCACAGGTAGG (SEQ ID NO: 4503) TGACTGGGGAGAAGTGAGAACTAGA (SEQ IDNO: 4504) hCV2557331 C/T GGGGCCATTTATTCTTCTTCAC (SEQ ID NO: 4505)GGGGCCATTTATTCTTCTTCAT (SEQ ID NO: 4506)GGAGTGGAAGGAATGGGGATTAAAG (SEQ ID NO: 4507) hCV2557469 A/CTGCTGGTGGCTTTAAAGAA (SEQ ID NO: 4508)TGCTGGTGGCTTTAAAGAC (SEQ ID NO: 4509)GGCAAAACCCCTTTTATTG (SEQ ID NO: 4510) hCV25591528 A/GTCCAAAAGGACCTGACAT (SEQ ID NO: 4511)TCCAAAAGGACCTGACAC (SEQ ID NO: 4512)GGCTGCAGAATGGAATTT (SEQ ID NO: 4513) hCV25596880 C/GCCTAGACAATAAAGATGGTCCTC (SEQ ID NO: 4514)CCTAGACAATAAAGATGGTCCTG (SEQ ID NO: 4515)CCAACTCTCTTCCTCTTGTCAT (SEQ ID NO: 4516) hCV25598594 A/GATATATTGACCGTTCTCCCAT (SEQ ID NO: 4517)ATATATTGACCGTTCTCCCAC (SEQ ID NO: 4518)GCCACCTCCAACCATATC (SEQ ID NO: 4519) hCV25603879 C/TGAAGTCATTCTGCTCTGC (SEQ ID NO: 4520)ATGAAGTCATTCTGCTCTGT (SEQ ID NO: 4521) TTTCCATCTCCTAACTCTTTTCTAG (SEQ IDNO: 4522) hCV25605897 G/T AAGGCAGGATGGGAGTG (SEQ ID NO: 4523)AAAGGCAGGATGGGAGTT (SEQ ID NO: 4524)CGTCAAAGCACTAATGTCATGT (SEQ ID NO: 4525) hCV25607193 C/TGCGCAAAAGGCAAGAC (SEQ ID NO: 4526) GCGCAAAAGGCAAGAT (SEQ ID NO: 4527)CCTTGGGACACACATTTACAG (SEQ ID NO: 4528) hCV25608818 A/GCTCAATGTCGTATTCACCTTCT (SEQ ID NO: 4529)CAATGTCGTATTCACCTTCC (SEQ ID NO: 4530) ACTCCAGGATTTTTCAAAGATTAT (SEQ IDNO: 4531) hCV25609975 A/C CTTTGAACCTTTTCACCACA (SEQ ID NO: 4532)TTTGAACCTTTTCACCACC (SEQ ID NO: 4533) GAGTGAGGAGGGAGAAAGTAAG (SEQ IDNO: 4534) hCV25610470 A/G CACAATCACCACGGTCT (SEQ ID NO: 4535)ACAATCACCACGGTCC (SEQ ID NO: 4536)CCTTCTGCATCAGCATCTTC (SEQ ID NO: 4537) hCV25610774 C/TGGGTCGGTGCAAGAGG (SEQ ID NO: 4538) GGGTCGGTGCAAGAGA (SEQ ID NO: 4539)GCACCTTGGTGGGTTTGT (SEQ ID NO: 4540) hCV25610819 A/TGGACGTGGACATGGAGT (SEQ ID NO: 4541) GGACGTGGACATGGAGA (SEQ ID NO: 4542)CGGCGCTCGTAGGTG (SEQ ID NO: 4543) hCV25614016 A/GAGTGGCCAAGAACACCA (SEQ ID NO: 4544) TGGCCAAGAACACCG (SEQ ID NO: 4545)GGTATGAGGCAAAGTTCCTG (SEQ ID NO: 4546) hCV25617571 C/TCCAGCAGTATGGACG (SEQ ID NO: 4547) TGCCAGCAGTATGGACA (SEQ ID NO: 4548)CCATCCAGCCTCAGGAAC (SEQ ID NO: 4549) hCV25618493 G/AGAGGCTGCGTATCC (SEQ ID NO: 4550) GGAGGCTGCGTATCT (SEQ ID NO: 4551)GTAGCTGTGCAGTGACAGTGT (SEQ ID NO: 4552) hCV25623265 A/GTGGAGGCTGATGGGTA (SEQ ID NO: 4553) GGAGGCTGATGGGTG (SEQ ID NO: 4554)CGCTTTGCAGCCATAACT (SEQ ID NO: 4555) hCV25629396 C/GAGAACGCCTATGAGGAGTG (SEQ ID NO: 4556)AAGAACGCCTATGAGGAGTC (SEQ ID NO: 4557)TTGGGTGGCACCATATG (SEQ ID NO: 4558) hCV25629476 A/GATCTCCTCGGCTGTCTT (SEQ ID NO: 4559) ATCTCCTCGGCTGTCTC (SEQ ID NO: 4560)AACCTCACCTGGCATGAG (SEQ ID NO: 4561) hCV25629492 A/GCCCACAGCCTGCGAT (SEQ ID NO: 4562) CCCACAGCCTGCGAC (SEQ ID NO: 4563)CCGCTTGAGGTCCACATA (SEQ ID NO: 4564) hCV25629888 C/GGCACCTTGCTGCTGTCTG (SEQ ID NO: 4565)GCACCTTGCTGCTGTCTC (SEQ ID NO: 4566)GCCCTGATCACTGCAAAAC (SEQ ID NO: 4567) hCV25630686 C/TAGGTTGTACCTGTAGCACTAAGAC (SEQ ID NO: 4568)TAGGTTGTACCTGTAGCACTAAGAT (SEQ ID NO: 4569)TGGGCTCCTCAGAGAAAATAT (SEQ ID NO: 4570) hCV25631989 C/TAAGATAAGCCTGTCACTGGTC (SEQ ID NO: 4571)AAGATAAGCCTGTCACTGGTT (SEQ ID NO: 4572)CAAGCCAGCCTAATAAACATAA (SEQ ID NO: 4573) hCV25636622 C/TTCTGTAGTCAACAGGAGAAGAGAC (SEQ ID NO: 4574)TCTGTAGTCAACAGGAGAAGAGAT (SEQ ID NO: 4575)GCTGGGTTTTGGTGAAGTT (SEQ ID NO: 4576) hCV25637309 A/TGGCCACTTTGCCTGAATA (SEQ ID NO: 4577)GGCCACTTTGCCTGAATT (SEQ ID NO: 4578) CGAAATGTTCATTTTTAAAGTCAGA (SEQ IDNO: 4579) hCV25640504 C/T CCAAGATCTTCAGCAACG (SEQ ID NO: 4580)ACCAAGATCTTCAGCAACA (SEQ ID NO: 4581)TGCAACCTCCACACAATCT (SEQ ID NO: 4582) hCV25640504 C/TCTAAGGTCTTCAGCAATG (SEQ ID NO: 5415)CTAAGGTCTTCAGCAATA (SEQ ID NO: 5416)TGCAACCTCCACACAATCT (SEQ ID NO: 4582) hCV25642473 C/TCCACATAGATTCCTAAGAACG (SEQ ID NO: 4583)ACCACATAGATTCCTAAGAACA (SEQ ID NO: 4584)CAAACACCATGGTTTTTCTTT (SEQ ID NO: 4585) hCV25643756 C/TCACTGCCATGCTCG (SEQ ID NO: 4586) ACACTGCCATGCTCA (SEQ ID NO: 4587)GCTGGCGCAGGAAGTAG (SEQ ID NO: 4588) hCV25644901 A/GCAGACCTGCAGCTTCA (SEQ ID NO: 4589) AGACCTGCAGCTTCG (SEQ ID NO: 4590)TGTAACCCATCAACTCTGTTTATC (SEQ ID NO: 4591) hCV25651076 A/GGATGCTGGCAAAGAACA (SEQ ID NO: 4592) ATGCTGGCAAAGAACG (SEQ ID NO: 4593)CAATCATCCACCTTTGTCTGT (SEQ ID NO: 4594) hCV25651174 A/GCGCTGCAGGGTCAT (SEQ ID NO: 4595) CGCTGCAGGGTCAC (SEQ ID NO: 4596)CCTCCCCGCAGAGAATTA (SEQ ID NO: 4597) hCV25652744 C/AAATGGTCCAGTTCCCTCTC (SEQ ID NO: 4598)CAATGGTCCAGTTCCCTCTA (SEQ ID NO: 4599)TGAAGTGTGAATGATGCTGATA (SEQ ID NO: 4600) hCV25742059 A/GCTGCCTCTTCTGCATTAGA (SEQ ID NO: 4601)TGCCTCTTCTGCATTAGG (SEQ ID NO: 4602)CCTTCACTGCCTGTTTCTCT (SEQ ID NO: 4603) hCV25745415 G/TTGACAGAGAATACTGGAAGATATG (SEQ ID NO: 4604)CTGACAGAGAATACTGGAAGATATT (SEQ ID NO: 4605)CCATCTTGGCCATGTTTAAT (SEQ ID NO: 4606) hCV25749177 G/ACAGTGCTGGAACCTGTAAGTC (SEQ ID NO: 4607)CAGTGCTGGAACCTGTAAGTT (SEQ ID NO: 4608)TGGAGTCAAAGGTTAAAACTCA (SEQ ID NO: 4609) hCV25753038 T/CGGAGCCACCTATGTTCTCTACT (SEQ ID NO: 4610)GAGCCACCTATGTTCTCTACC (SEQ ID NO: 4611)TCCCTCTTTGCTCATTCATC (SEQ ID NO: 4612) hCV25767229 C/TGTGTGGCAATGAAGTCCC (SEQ ID NO: 4613)AGTGTGGCAATGAAGTCCT (SEQ ID NO: 4614) GCAGTGCTCGTTACATGAAAGATC (SEQ IDNO: 4615) hCV25767417 A/G AGCCCCTTGTCTTCCAT (SEQ ID NO: 4616)AGCCCCTTGTCTTCCAC (SEQ ID NO: 4617)AAAGCAGTTCGACAAAATCTTA (SEQ ID NO: 4618) hCV25770061 A/CCCAAGCGACAGTCATAGTCT (SEQ ID NO: 4619)CAAGCGACAGTCATAGTCG (SEQ ID NO: 4620)GTGCTGAATGTTTGCTCTGTGTATCTAC (SEQ ID NO: 4621) hCV25922320 A/GCTCGCAGCGGTCAGT (SEQ ID NO: 4622) TCGCAGCGGTCAGC (SEQ ID NO: 4623)GCTGGCGGGAATTTCT (SEQ ID NO: 4624) hCV25922440 C/TCGAACTCTTCAAGGTGGTTG (SEQ ID NO: 4625)CCGAACTCTTCAAGGTGGTTA (SEQ ID NO: 4626)CCATGCATGCTTCAGGTAAG (SEQ ID NO: 4627) hCV25922816 A/GTGGCACTCAGGGCAT (SEQ ID NO: 4628) TGGCACTCAGGGCAC (SEQ ID NO: 4629)CCAAAGAGGACTGACAACTGTA (SEQ ID NO: 4630) hCV25924894 A/GGGGAAGTTCTTTCTTGTATATTCAA (SEQ ID NO: 4631)GGGAAGTTCTTTCTTGTATATTCAG (SEQ ID NO: 4632)TGCTGTCTTTGCCTCACTAAT (SEQ ID NO: 4633) hCV25925481 A/GAATCAGCATTTTTGTCAAAGA (SEQ ID NO: 4634)ATCAGCATTTTTGTCAAAGG (SEQ ID NO: 4635)GGCTTGTGACCTCATTGTTT (SEQ ID NO: 4636) hCV25925974 G/CAAAGCAAAGGCACAGAGAG (SEQ ID NO: 4637)AAAGCAAAGGCACAGAGAC (SEQ ID NO: 4638)TGCCGTGCTGAGTTAATG (SEQ ID NO: 4639) hCV25926178 C/GGCTTTATCAGAGACTCTGAAGC (SEQ ID NO: 4640)GCTTTATCAGAGACTCTGAAGG (SEQ ID NO: 4641)CCAAGGCCACGGATATC (SEQ ID NO: 4642) hCV2592654 A/CCAGTAAGCTGGAGAGTGGA (SEQ ID NO: 4643)AGTAAGCTGGAGAGTGGC (SEQ ID NO: 4644) TGGGAGGTGGATAAGGCAGATAAG (SEQ IDNO: 4645) hCV2592662 A/G GTTTGTGGGTTTTGTGGGA (SEQ ID NO: 4646)TTTGTGGGTTTTGTGGGG (SEQ ID NO: 4647) CAGAGCAGCTTTCAAACTTTCTGAA (SEQ IDNO: 4648) hCV25926643 G/A CCTGGTTAGCTTTACCTTACG (SEQ ID NO: 4649)CCCTGGTTAGCTTTACCTTACA (SEQ ID NO: 4650)CCCTTGCCATCCACACT (SEQ ID NO: 4651) hCV25926771 C/TGGCCTTGGTCTCGC (SEQ ID NO: 4652) TGGCCTTGGTCTCGT (SEQ ID NO: 4653)TGCAGATCAGCTTGAAGAACTA (SEQ ID NO: 4654) hCV2592715 A/TCTGACCTTTCCTTTATTAAGCATCTATA (SEQ IDTGACCTTTCCTTTATTAAGCATCTATT (SEQ ID NO: 4656)GTGCCGCTGTTTCCTCATGT (SEQ ID NO: 4657) NO: 4655) hCV25927459 G/TGGCTGTTGCTCCTCTTATG (SEQ ID NO: 4658)TGGCTGTTGCTCCTCTTATT (SEQ ID NO: 4659) GGACCTGTCAATCTTGGTCATCTAT (SEQ IDNO: 4660) hCV2592759 A/C TCCTCTCAGATAGTGTGAATACAATA (SEQ IDCCTCTCAGATAGTGTGAATACAATC (SEQ ID NO: 4662)CAACTGAGGCAAATACTGTGCTAACT (SEQ ID NO: 4661) NO: 4663) hCV25928135 C/TTTTCACCGTATTAGCCAGG (SEQ ID NO: 4664)GTTTCACCGTATTAGCCAGA (SEQ ID NO: 4665)CCCATAGTGGCCTCAATAGT (SEQ ID NO: 4666) hCV25928538 C/GTCCACTGTTTTTGAACGC (SEQ ID NO: 4667)TCCACTGTTTTTGAACGG (SEQ ID NO: 4668) TAATTGCAAGAATATTGAAAGACA (SEQ IDNO: 4669) hCV25930271 C/T GAATCTCATGTTCAGGAAATG (SEQ ID NO: 4670)CGAATCTCATGTTCAGGAAATA (SEQ ID NO: 4671)GCCATGGCCCATAAAAC (SEQ ID NO: 4672) hCV25932224 T/GAGCCACTAAGCTCAAACTCTTT (SEQ ID NO: 4673)GCCACTAAGCTCAAACTCTTG (SEQ ID NO: 4674)CCCTAAAACCAAAGACGTATGT (SEQ ID NO: 4675) hCV25941408 G/TCATGGAGTCAACTCTTGAGG (SEQ ID NO: 4676)GCATGGAGTCAACTCTTGAGT (SEQ ID NO: 4677)GGCTGTGCTTTGTCTGATCT (SEQ ID NO: 4678) hCV25942539 G/AGGATCCGACCGTTGAG (SEQ ID NO: 4679) GGATCCGACCGTTGAA (SEQ ID NO: 4680)TCATTTTGAACTCATTTTTTCTAGA (SEQ ID NO: 4681) hCV25943180 T/CGGTGGTCTTCCAGTCCTT (SEQ ID NO: 4682)GGTGGTCTTCCAGTCCTC (SEQ ID NO: 4683)TTGCTCCCTGCGAGTAAG (SEQ ID NO: 4684) hCV25965660 A/GGGCCTGGTGGAAGTGAT (SEQ ID NO: 4685) GGCCTGGTGGAAGTGAC (SEQ ID NO: 4686)AGTGTCAAGGTAATCTGGTTTTT (SEQ ID NO: 4687) hCV25972680 A/GGCAGGCCTTTCTCAGAAT (SEQ ID NO: 4688)GCAGGCCTTTCTCAGAAC (SEQ ID NO: 4689) CAGGAAGAGAAGAAGTCACTTGT (SEQ IDNO: 4690) hCV25996298 G/T CAGAGGCTGCTCCGC (SEQ ID NO: 4691)ACAGAGGCTGCTCCGA (SEQ ID NO: 4692) GGGTTTGTGGGCTCTTC (SEQ ID NO: 4693)hCV26000635 C/A TGCTGGAGCAATTGAGAG (SEQ ID NO: 4694)CTGCTGGAGCAATTGAGAT (SEQ ID NO: 4695)TCTTCCCCTCGTTTCTTTC (SEQ ID NO: 4696) hCV260164 G/TACAGGTCACTGGGATTGG (SEQ ID NO: 4697)ACAGGTCACTGGGATTGT (SEQ ID NO: 4698) CTGGACAGTGTTTGGAAGGTCATA (SEQ IDNO: 4699) hCV2604332 G/T GCAAATCAAGTAAAAGATCTGTTTC (SEQ ID NO: 4700)GCAAATCAAGTAAAAGATCTGTTTA (SEQ ID NO: 4701)CTGCAGCAGCTAAATGTCA (SEQ ID NO: 4702) hCV26294850 C/TGCCCAAGCGGAAGGTACGACTTTCCGGCTGAAAGCCGCATACCTTGCCAGTAGCGATGCGGCGGCTGAAAGCCA GCAGCACGAACTGC (SEQ ID NO: 4705)G (SEQ ID NO: 4703) (SEQ ID NO: 4704) hCV2632070 A/GGACTAAAGTTCTGAGCCAATCAA (SEQ ID NO: 4706)ACTAAAGTTCTGAGCCAATCAG (SEQ ID NO: 4707) GCCCTTTGTTCCTCGGTTTAGAG (SEQ IDNO: 4708) hCV2632498 C/G CAATTGAGGTCCAGGAGC (SEQ ID NO: 4709)CAATTGAGGTCCAGGAGG (SEQ ID NO: 4710)TGGTGCAAACAGCTCTTCT (SEQ ID NO: 4711) hCV2632544 C/TACTGACCCTTCACACATTTAC (SEQ ID NO: 4712)GTAACTGACCCTTCACACATTTAT (SEQ ID NO: 4713)TGAGCCATCGTGCCTAGCTA (SEQ ID NO: 4714) hCV2633049 G/TCTTCTAGGCTCTGTGGTCC (SEQ ID NO: 4715)CTTCTAGGCTCTGTGGTCA (SEQ ID NO: 4716) CCACGTGCCCATGAAG (SEQ ID NO: 4717)hCV2658421 A/C CTCTCTTTCAGCATCTTGTAAAT (SEQ ID NO: 4718)CTCTCTTTCAGCATCTTGTAAAG (SEQ ID NO: 4719)TGCAGAAGAAAGAAACTTTATCAC (SEQ ID NO: 4720) hCV26660340 C/GTGTGTCCAAAGGGACCAC (SEQ ID NO: 4721)TGTGTCCAAAGGGACCAG (SEQ ID NO: 4722) GACCCCATTTTCCTGGACCATTAAG (SEQ IDNO: 4723) hCV26683367 C/G CCTATTAAGATGAGAACCTCAACAC (SEQ ID NO: 4724)CCTATTAAGATGAGAACCTCAACAG (SEQ ID NO: 4725)GGAGGTGGAAGAGCATTGAAACT (SEQ ID NO: 4726) hCV26683368 C/TTGTAAAATGCCTGTCACGG (SEQ ID NO: 4727)GTGTAAAATGCCTGTCACGA (SEQ ID NO: 4728) CGATGACATTCTTGGTCTGTACACT (SEQ IDNO: 4729) hCV2680532 A/C GGGCCTCACCTTGGT (SEQ ID NO: 4730)GGGCCTCACCTTGGG (SEQ ID NO: 4731) GCCTCCCCAGATTGATGTCT (SEQ ID NO: 4732)hCV26809148 A/G CATCATGGTGTTCTTGCCT (SEQ ID NO: 4733)ATCATGGTGTTCTTGCCC (SEQ ID NO: 4734) CATTATCTGAAATGTTTCATTGTAGA (SEQ IDNO: 4735) hCV26898946 C/T TGGGTGGCAGTCCC (SEQ ID NO: 4736)GTGGGTGGCAGTCCT (SEQ ID NO: 4737)GGGGACAGGTATGCATGTCAT (SEQ ID NO: 4738) hCV27157435 C/TGGAACTTAATTGCTTGATACTATCAC (SEQ IDGGAACTTAATTGCTTGATACTATCAT (SEQ ID NO: 4740)GACACCACCGTCCTACACTG (SEQ ID NO: 4741) NO: 4739) hCV27157439 A/CGTAACTAACACTCAGAAGTACATTTT (SEQ IDGTAACTAACACTCAGAAGTACATTTG (SEQ ID NO: 4743)GTTGAGGCTGCAGTGAGCTATAAT (SEQ ID NO: 4742) NO: 4744) hCV2741051 C/TGCAGCCAGTTTCTCCC (SEQ ID NO: 4745) TGCAGCCAGTTTCTCCT (SEQ ID NO: 4746)CATGAAATGCTTCCAGGTATT (SEQ ID NO: 4747) hCV2741083 C/TGTTCCAACCAGAAGAGAATG (SEQ ID NO: 4748)GGTTCCAACCAGAAGAGAATA (SEQ ID NO: 4749)CTTGCCCCCAACAGTTAG (SEQ ID NO: 4750) hCV27422538 C/GGCAATCTCTCCTTCCTCTCC (SEQ ID NO: 4751)GCAATCTCTCCTTCCTCTCG (SEQ ID NO: 4752) ACACACACACCTCCACAAATACTAA (SEQ IDNO: 4753) hCV27457080 C/T AAATAGGTCGTTCTGACATAAAAG (SEQ ID NO: 4754)AAATAGGTCGTTCTGACATAAAAA (SEQ ID NO: 4755)CCCACTCCACCATCTGTATAG (SEQ ID NO: 4756) hCV27462774 A/GAAGATCATGATTTATCTTGGTTCCTA (SEQ IDAGATCATGATTTATCTTGGTTCCTG (SEQ ID NO: 4758)GGTGGTCAGCACATGACTTCT (SEQ ID NO: 4759) NO: 4757) hCV27480853 C/TCCTGTTAGGTGTGTTGCTTTAAC (SEQ ID NO: 4760)CCTGTTAGGTGTGTTGCTTTAAT (SEQ ID NO: 4761)GCTTACGCCATTTTCTGTCGGTATTT (SEQ ID NO: 4762) hCV2762168 C/TCCCCATGGTTTGTTGTTGC (SEQ ID NO: 4763)CCCCATGGTTTGTTGTTGT (SEQ ID NO: 4764) CGACTTCAGTGACCACACATAACA (SEQ IDNO: 4765) hCV2769554 A/G TCCGTTGTTCTCAGGGAT (SEQ ID NO: 4766)TCCGTTGTTCTCAGGGAC (SEQ ID NO: 4767)GGTTCCTGGAGGCATGTC (SEQ ID NO: 4768) hCV2781953 G/TACATTGCGGTTATTGCTAGTG (SEQ ID NO: 4769)ACATTGCGGTTATTGCTAGTT (SEQ ID NO: 4770) CACCTGCCTCTCTCAAAGAATAGC (SEQ IDNO: 4771) hCV27884601 C/T GGAATATTTGGGTTTGTTTCACC (SEQ ID NO: 4772)GGAATATTTGGGTTTGTTTCACT (SEQ ID NO: 4773)CTGGGACTGTCTATTTTCTTTCATTCAACC (SEQ ID NO: 4774) hCV27958354 C/TGCTATGAGGAGAACACAAGAATATAC (SEQ IDGCTATGAGGAGAACACAAGAATATAT (SEQ ID NO: 4776)CATTCCCTCTGCCCCTTCTTAGATA (SEQ ID NO: 4775) NO: 4777) hCV27970553 C/TACCTAAACTTTGGTATCACCG (SEQ ID NO: 4778)CACCTAAACTTTGGTATCACCA (SEQ ID NO: 4779)CTCACCCGCTGATATTTGTTTAACCT (SEQ ID NO: 4780) hCV28008078 C/TCTGTCACAAGCAACAGAAAG (SEQ ID NO: 4781)TCTGTCACAAGCAACAGAAAA (SEQ ID NO: 4782) CGAGGAGGAGATAACTGGATGTGT (SEQ IDNO: 4783) hCV28023091 C/T TTCAGTTCTTTGCAGTAATAAACAG (SEQ ID NO: 4784)TTCAGTTCTTTGCAGTAATAAACAA (SEQ ID NO: 4785)CATTTGTCTGAGGGTTCACTTGTTGA (SEQ ID NO: 4786) hCV2822674 A/GGATGCTGGGTGGATGTT (SEQ ID NO: 4787) GATGCTGGGTGGATGTC (SEQ ID NO: 4788)TGTGGCCCTGAGAATGTAC (SEQ ID NO: 4789) hCV282793 C/TATCTATTCACAAACACATGAACAAG (SEQ ID NO: 4790)ATCTATTCACAAACACATGAACAAA (SEQ ID NO: 4791)GAGACACCCAAGCAAACTGAACTTAC (SEQ ID NO: 4792) hCV2829795 A/GGTTTCTCTCCAGTATGAATTCTTT (SEQ ID NO: 4793)GTTTCTCTCCAGTATGAATTCTTC (SEQ ID NO: 4794)AATTCATTCTGGAGAGAAATCTTAC (SEQ ID NO: 4795) hCV28960526 A/TTGAAGGCACCTGTCATCAT (SEQ ID NO: 4796)TGAAGGCACCTGTCATCAA (SEQ ID NO: 4797) CTCCTGGTGGGCCTTTTGAAATA (SEQ IDNO: 4798) hCV28974083 A/G TTCACTTCAAGCTTCCATAGTTAT (SEQ ID NO: 4799)TCACTTCAAGCTTCCATAGTTAC (SEQ ID NO: 4800)CCTCCTCTTCTCATCAATCCCAAATTAGT (SEQ ID NO: 4801) hCV28993059 A/GGAATGAGTAAGGGAAGAGGAAAA (SEQ ID NO: 4802)GAATGAGTAAGGGAAGAGGAAAG (SEQ ID NO: 4803)GCTGAATTGTCTGACGGAATCT (SEQ ID NO: 4804) hCV29011391 A/GGCTCGGAAAAGCCAAGAAA (SEQ ID NO: 4805)GCTCGGAAAAGCCAAGAAG (SEQ ID NO: 4806)GATCCAGATTTTGTCAAAGCCACTAGA (SEQ ID NO: 4807) hCV29033518 A/TGCATTATACATGTGCAGTCACATT (SEQ ID NO: 4808)GCATTATACATGTGCAGTCACATA (SEQ ID NO: 4809)CCACCATGGCTGTGTCTTGT (SEQ ID NO: 4810) hCV29135108 A/CGGAGTGCTTTTATGGCAAAA (SEQ ID NO: 4811)GGAGTGCTTTTATGGCAAAC (SEQ ID NO: 4812)GCTGATAGTGCAAGTTAGCAACATAGT (SEQ ID NO: 4813) hCV29195255 A/CTCCAGCAATTCCACTTCCA (SEQ ID NO: 4814)CCAGCAATTCCACTTCCC (SEQ ID NO: 4815) AGAACTAGCAAAGCACCTCTGTAGAA (SEQ IDNO: 4816) hCV29195260 A/G CATTATCTAGTTTCTTTACTTGTCTTCT (SEQ IDCATTATCTAGTTTCTTTACTTGTCTTCC (SEQ ID AGCATCTTCTGTGTCCAGCTAAGT (SEQ IDNO: 4817) NO: 4818) NO: 4819) hCV2932115 C/TTGGACGTGGGCTTTTTC (SEQ ID NO: 4820) TGGACGTGGGCTTTTTT (SEQ ID NO: 4821)GCTGCAGCCCTTTTTCTC (SEQ ID NO: 4822) hCV29322781 A/GAGATATCCACTACTCTTCTTCTCAA (SEQ ID NO: 4823)AGATATCCACTACTCTTCTTCTCAG (SEQ ID NO: 4824)CTTAAGCCAGTCCTGCACAACTAG (SEQ ID NO: 4825) hCV29368919 C/TGCTTCAAGAGGATAAAGTAAAACAGAG (SEQ ID GCTTCAAGAGGATAAAGTAAAACAGAA (SEQ IDGATATAACCTGTCACTACACTGGACTGAA (SEQ ID NO: 4826) NO: 4827) NO: 4828)hCV29480044 C/T GGTGGGCCTTTTGAAATAAAC (SEQ ID NO: 4829)TGGTGGGCCTTTTGAAATAAAT (SEQ ID NO: 4830) CTTGAAGTGAAGGCACCTGTCAT (SEQ IDNO: 4831) hCV2948766 A/G ACAATAACCCTTCTAATTGCACA (SEQ ID NO: 4832)CAATAACCCTTCTAATTGCACG (SEQ ID NO: 4833)GTGTTGCTGAAATCATGGAGTCTGAT (SEQ ID NO: 4834) hCV2960489 A/GCCCACCATCCACTTCCT (SEQ ID NO: 4835) CCCACCATCCACTTCCC (SEQ ID NO: 4836)CTCCAGCGTTGGGGATGATG (SEQ ID NO: 4837) hCV2966448 A/GGTTAAACCTTCTTTATCTCCTCCTT (SEQ ID NO: 4838)GTTAAACCTTCTTTATCTCCTCCTC (SEQ ID NO: 4839)CGCTTCGCCTTGGGATATG (SEQ ID NO: 4840) hCV29684678 C/GCAGCTACACTTCAGTCTACTTAG (SEQ ID NO: 4841)CAGCTACACTTCAGTCTACTTAC (SEQ ID NO: 4842)GAGAAGGAGACTGGAGACAGATATGAC (SEQ ID NO: 4843) hCV29809835 A/CGTCTCGGAAGCAATGTTCTA (SEQ ID NO: 4844)TCTCGGAAGCAATGTTCTC (SEQ ID NO: 4845)GCTTCTGCCACCCCTGTAAAT (SEQ ID NO: 4846) hCV29819064 C/TTCGCTTTGAAACACTCTGC (SEQ ID NO: 4847)CTCGCTTTGAAACACTCTGT (SEQ ID NO: 4848)CTGTGGCTTCAGGCTTTACAGT (SEQ ID NO: 4849) hCV2983035 A/GTTGGACCCTCACATGAAA (SEQ ID NO: 4850)TTGGACCCTCACATGAAG (SEQ ID NO: 4851) GCCATTTTCCACAATAAATATTT (SEQ IDNO: 4852) hCV2983036 C/G GCTGACTTTTTTGCTCTTTC (SEQ ID NO: 4853)GCTGACTTTTTTGCTCTTTG (SEQ ID NO: 4854) GCCATTTTCCACAATAAATATTT (SEQ IDNO: 4855) hCV2987229 C/T GGAGGGAGGCAACCAC (SEQ ID NO: 4856)GGAGGGAGGCAACCAT (SEQ ID NO: 4857) TGCCCGATAAACGTGAGGTAGAA (SEQ IDNO: 4858) hCV2987250 C/G ACTGCTCCAAGATAGAGGTAC (SEQ ID NO: 4859)ACTGCTCCAAGATAGAGGTAG (SEQ ID NO: 4860) CAGCATTTGTGAGAGGAGCTGTTT (SEQ IDNO: 4861) hCV29873524 C/T TCATCAAACCACTCAAGCTAC (SEQ ID NO: 4862)TTTCATCAAACCACTCAAGCTAT (SEQ ID NO: 4863)CACTCAAATGGAAGAGTCATTGGTGAAT (SEQ ID NO: 4864) hCV2992252 T/CCCCTGTGATTGGCCAT (SEQ ID NO: 4865) CCCTGTGATTGGCCAC (SEQ ID NO: 4866)CCTGCTCGCTCTGTCAC (SEQ ID NO: 4867) hCV29945430 G/TGAGCTCATGTGCATTATAAACG (SEQ ID NO: 4868)AGAGCTCATGTGCATTATAAACT (SEQ ID NO: 4869)CCGCCTACTGACTACCTGTCTA (SEQ ID NO: 4870) hCV29952522 A/GACTGGAAAGATGACACATCTACA (SEQ ID NO: 4871)CTGGAAAGATGACACATCTACG (SEQ ID NO: 4872) GGGCTACACCCAAAGGCTAAATC (SEQ IDNO: 4873) hCV30136303 C/G TCACCCCACTCTGCTATAG (SEQ ID NO: 4874)TCACCCCACTCTGCTATAC (SEQ ID NO: 4875)CAAAGGCTGGGAAGGGTATGTATATTG (SEQ ID NO: 4876) hCV30233466 A/GGCGCCCGGATGGAAT (SEQ ID NO: 4877) GCGCCCGGATGGAAC (SEQ ID NO: 4878)ACGCCCACTCCAGTTACTAAACA (SEQ ID NO: 4879) hCV3026189 C/TCTTCTTGCCCTTCAGCTC (SEQ ID NO: 4880)CTTCTTGCCCTTCAGCTT (SEQ ID NO: 4881)CCCAGTTCTGAGATGTGTATGT (SEQ ID NO: 4882) hCV30264691 G/TTTCTCCTGAAGAATTGTAAGCC (SEQ ID NO: 4883)TTTCTCCTGAAGAATTGTAAGCA (SEQ ID NO: 4884)GAAGTTAGCCAATCTTGTCATCTTTTCACT (SEQ ID NO: 4885) hCV30287627 A/TAATGCAAAATGCAAACTGTCTAA (SEQ ID NO: 4886)CAATGCAAAATGCAAACTGTCTAT (SEQ ID NO: 4887)TGGAGTTGTCGTCCTGTGGATAAT (SEQ ID NO: 4888) hCV30454150 C/TTCTAGCAGATTTGTATCAGAACC (SEQ ID NO: 4889)TAATCTAGCAGATTTGTATCAGAACT (SEQ ID NO: 4890)GCGACCCTCTCTGGTTAAACA (SEQ ID NO: 4891) hCV30467730 C/TCTCTACTGTTTAGAATCGTTTTCAAC (SEQ IDCTCTACTGTTTAGAATCGTTTTCAAT (SEQ ID NO: 4893)CCAGCGGTAATTGGAGCAATCTTA (SEQ ID NO: 4892) NO: 4894) hCV30534667 A/GAGAACAACTCAAAGGTGCAAA (SEQ ID NO: 4895)AGAACAACTCAAAGGTGCAAG (SEQ ID NO: 4896)ACATGACCTGTTCTAACTGGGAGTTATG (SEQ ID NO: 4897) hCV30574599 C/TCCATGCACACTTTAATGTGTAC (SEQ ID NO: 4898)TCCATGCACACTTTAATGTGTAT (SEQ ID NO: 4899)CCCAAACACAACAGGCTAGAACAAAT (SEQ ID NO: 4900) hCV30586985 A/GTCGGTGATTGGTACAAGAGTAA (SEQ ID NO: 4901)CGGTGATTGGTACAAGAGTAG (SEQ ID NO: 4902)GCTGGAATGGTACTCCTGAGTATGT (SEQ ID NO: 4903) hCV30606396 C/TACATTTGCTCATTCTGTACTCC (SEQ ID NO: 4904)CACATTTGCTCATTCTGTACTCT (SEQ ID NO: 4905)CAAGAGATCTGGAGGTGGGGATTAT (SEQ ID NO: 4906) hCV3068176 A/GTACCACAGCTTGCTCACAT (SEQ ID NO: 4907)TACCACAGCTTGCTCACAC (SEQ ID NO: 4908)TTTCCCCCATTTTTCAGTT (SEQ ID NO: 4909) hCV30764105 C/GGGCCCTGAACCTTTCAG (SEQ ID NO: 4910) GGCCCTGAACCTTTCAC (SEQ ID NO: 4911)CGAATTAGTAAGTTACCAGTGACATCAGC (SEQ ID NO: 4912) hCV3086932 G/TTGTATCGAGAGAGAAAGATAGTTTG (SEQ ID NO: 4913)TTGTATCGAGAGAGAAAGATAGTTTT (SEQ ID NO: 4914)CTCCACCAAATACCCTCATCTGTTCT (SEQ ID NO: 4915) hCV3086948 C/TCTGGCATATTTTGAAGTATTCTCTG (SEQ ID NO: 4916)CTCTGGCATATTTTGAAGTATTCTCTA (SEQ ID CTCTGGAAAGGGAAATGTCACTCTA (SEQ IDNO: 4917) NO: 4918) hCV3086950 A/GCTCCTTGCCTCAAATGATTTCT (SEQ ID NO: 4919)TCCTTGCCTCAAATGATTTCC (SEQ ID NO: 4920)TTCAGTCATACTCATGGTCCAAATCTCATT (SEQ ID NO: 4921) hCV3086961 A/CAAGCATCCAGAGCCTCTTAT (SEQ ID NO: 4922)AGCATCCAGAGCCTCTTAG (SEQ ID NO: 4923) GCTGTCCACCTGTCACTTTCATAAT (SEQ IDNO: 4924) hCV3086983 C/T GCATAACTAAACTATAGTGTACAGACAC (SEQ IDGCATAACTAAACTATAGTGTACAGACAT (SEQ IDGACGTGGCCAGCCATCTTC (SEQ ID NO: 4927) NO: 4925) NO: 4926) hCV3087000 A/GGAGCATAGAAACAATTTTGTTCCAT (SEQ ID NO: 4928)AGCATAGAAACAATTTTGTTCCAC (SEQ ID NO: 4929)AGTGTGTGGTTTCAGCAGTACTAGATT (SEQ ID NO: 4930) hCV3087003 C/GCCTGGGCAAGATGGTAAAAC (SEQ ID NO: 4931)CCTGGGCAAGATGGTAAAAG (SEQ ID NO: 4932)CTGGGCTCAGGCAATCCTA (SEQ ID NO: 4933) hCV3087008 A/CCAGAGTCCTTCAGTAAACTTCTTT (SEQ ID NO: 4934)CAGAGTCCTTCAGTAAACTTCTTG (SEQ ID NO: 4935)CCACCTTCTTTCAACCCAAATTTTCTC (SEQ ID NO: 4936) hCV3087015 C/GACAGCTTTTACTTACCTTTGATAGAG (SEQ IDACAGCTTTTACTTACCTTTGATAGAC (SEQ ID NO: 4938)AGCTGAGTGGGAGAGAAGAATACAC (SEQ ID NO: 4937) NO: 4939) hCV3087016 A/CAGCACTCCATAACTTTACCCT (SEQ ID NO: 4940)GCACTCCATAACTTTACCCG (SEQ ID NO: 4941)GACTACACACAAGATCAACTAATAGAAATACTGC (SEQ ID NO: 4942) hCV3111721 C/TACCGTTGTCCTCCC (SEQ ID NO: 4943) GACCGTTGTCCTCCT (SEQ ID NO: 4944)GCCTCTAGCACGATGGATAG (SEQ ID NO: 4945) hCV3111822 C/TAAACCTTCCTACACAGAACTTC (SEQ ID NO: 4946)AAACCTTCCTACACAGAACTTT (SEQ ID NO: 4947) CTGGTGGTGGTGAGAAGAACAT (SEQ IDNO: 4948) hCV31145250 A/C CTGAGCCACCTTATCTGTTAAAA (SEQ ID NO: 4949)TGAGCCACCTTATCTGTTAAAC (SEQ ID NO: 4950)CACAGGGTTGTTAACCTTGGTTTAG (SEQ ID NO: 4951) hCV31161091 A/GACACCTGCTGACTATCCAAT (SEQ ID NO: 4952)CACCTGCTGACTATCCAAC (SEQ ID NO: 4953) CATCGTGATCCTGCCAAGTAGAGA (SEQ IDNO: 4954) hCV31237961 A/C GGCGAAGACAAAATTATATTTCAACT (SEQ IDGGCGAAGACAAAATTATATTTCAACG (SEQ ID NO: 4956)CCAGGAAGCTCAGGCAAATTTGA (SEQ ID NO: 4955) NO: 4957) hCV3135085 G/TCTGGAAATGGTTATGGGC (SEQ ID NO: 4958)TACTGGAAATGGTTATGGGA (SEQ ID NO: 4959) TTTATAGGCGTGAAACTAATTCTC (SEQ IDNO: 4960) hCV31356445 G/T GCCTGTGGTTGTCTTCCC (SEQ ID NO: 4961)GCCTGTGGTTGTCTTCCA (SEQ ID NO: 4962)ACTTCCTCAGGTCTGCTGTGT (SEQ ID NO: 4963) hCV31466171 A/GCTCCAATCCCACATTTCCA (SEQ ID NO: 4964)TCCAATCCCACATTTCCG (SEQ ID NO: 4965) CCATGACTCTTCAGAACCTGTTTGT (SEQ IDNO: 4966) hCV3152623 A/C CTGCAGAAACGATCAGTGT (SEQ ID NO: 4967)TGCAGAAACGATCAGTGG (SEQ ID NO: 4968)TGCTTCTGTCATTCTTTCTGAT (SEQ ID NO: 4969) hCV31528409 A/GTGCCTGGACTGTGTTCTT (SEQ ID NO: 4970)TGCCTGGACTGTGTTCTC (SEQ ID NO: 4971) GAGGCAGAGGTTTCAGTGAGTAGA (SEQ IDNO: 4972) hCV3168675 A/G TCTCCCACTGTGTTCCTA (SEQ ID NO: 4973)CTCCCACTGTGTTCCTG (SEQ ID NO: 4974) TGCCAGGGATTGGTTGCTTAATAC (SEQ IDNO: 4975) hCV3170445 C/T GCTGCAAAAATGAACAACAC (SEQ ID NO: 4976)GCTGCAAAAATGAACAACAT (SEQ ID NO: 4977)GAATGCATAGCTGATCTCAAGA (SEQ ID NO: 4978) hCV3170459 C/TGACTGTCCTGATTGGAATCC (SEQ ID NO: 4979)TGACTGTCCTGATTGGAATCT (SEQ ID NO: 4980) GGCATTTTGGTATCATTTTGTTA (SEQ IDNO: 4981) hCV3179059 G/T CATCCTCGTGGGAAGTG (SEQ ID NO: 4982)CATCCTCGTGGGAAGTT (SEQ ID NO: 4983)CCAACCTCTGCTCTCTGATAAT (SEQ ID NO: 4984) hCV3180404 A/GCAGCAGAGCAGCCTTAA (SEQ ID NO: 4985) CAGCAGAGCAGCCTTAG (SEQ ID NO: 4986)TGATGCTGGAAGCACTTCT (SEQ ID NO: 4987) hCV3181997 A/GTGGATCCTGACTTTGTGAAAT (SEQ ID NO: 4988)TGGATCCTGACTTTGTGAAAC (SEQ ID NO: 4989) GGAATCTGAAGGAGACATTTTTAC (SEQ IDNO: 4990) hCV3187716 A/C CCTTCAATTCTGAAAAGTAGCTAAT (SEQ ID NO: 4991)CCTTCAATTCTGAAAAGTAGCTAAG (SEQ ID NO: 4992)TTTGAGGTTGAGTGACATGTTC (SEQ ID NO: 4993) hCV31954792 A/CCCGGAGGCTAGATTATTACCT (SEQ ID NO: 4994)CGGAGGCTAGATTATTACCG (SEQ ID NO: 4995) ATCCCATTCCCTCCCTTCACATAA (SEQ IDNO: 4996) hCV3201490 A/G GCAGTCCTGCCGTACT (SEQ ID NO: 4997)GCAGTCCTGCCGTACC (SEQ ID NO: 4998) ACTGCTCAACTACCTGGTGGATAAG (SEQ IDNO: 4999) hCV32055474 C/G GAACAGTTCAGATTTACAAGTGC (SEQ ID NO: 5000)AGAACAGTTCAGATTTACAAGTGG (SEQ ID NO: 5001)CCACTGTTAACATTTGTTGTATGGTCAGT (SEQ ID NO: 5002) hCV32055477 A/GGAGTGCTAACAGAGTAATTACCAA (SEQ ID NO: 5003)GAGTGCTAACAGAGTAATTACCAG (SEQ ID NO: 5004)AAGGTCTCACCTGGTATGCTGTATTTT (SEQ ID NO: 5005) hCV32055527 A/CACACCCCAACGTCATCA (SEQ ID NO: 5006) ACACCCCAACGTCATCC (SEQ ID NO: 5007)AAGCCTTGGAAAGCGAAACTGT (SEQ ID NO: 5008) hCV32055581 A/GGTGAGACAGCAAACACTATACA (SEQ ID NO: 5009)TGAGACAGCAAACACTATACG (SEQ ID NO: 5010) TTCCCGAAGAGCTGGAATTACAGT (SEQ IDNO: 5011) hCV32055595 C/T ACCATCTACTATGAGCCTCC (SEQ ID NO: 5012)AAACCATCTACTATGAGCCTCT (SEQ ID NO: 5013)GTCTGTTGCCCATGGATGATTACA (SEQ ID NO: 5014) hCV32055596 A/GGAAACTAGTTCTGTCTTCTAGCAT (SEQ ID NO: 5015)GAAACTAGTTCTGTCTTCTAGCAC (SEQ ID NO: 5016)GGGTCACAGACTTAGCCAGTGATA (SEQ ID NO: 5017) hCV32055625 C/TCTTCAGACAAGCTGTCCTG (SEQ ID NO: 5018)ATCTTCAGACAAGCTGTCCTA (SEQ ID NO: 5019) GAAACCTAATTGGCCCAGGTCATC (SEQ IDNO: 5020) hCV32055654 A/G TGATGCACAAGAGTGTTTACTTT (SEQ ID NO: 5021)TGATGCACAAGAGTGTTTACTTC (SEQ ID NO: 5022)GAGCTTGGATTAGGCAATGGTTTCT (SEQ ID NO: 5023) hCV3215409 A/GGTGGCTCATTACCAATCTCTT (SEQ ID NO: 5024)GTGGCTCATTACCAATCTCTC (SEQ ID NO: 5025)GGGCTCCATCAACATCAC (SEQ ID NO: 5026) hCV3219460 G/TGCAGGCCCCAGATGAG (SEQ ID NO: 5027) GCAGGCCCCAGATGAT (SEQ ID NO: 5028)CCATCCCACCCAGTCAA (SEQ ID NO: 5029) hCV323070 A/GGCCCAGAAAGATGAGTTCA (SEQ ID NO: 5030)GCCCAGAAAGATGAGTTCG (SEQ ID NO: 5031) TGTCCCTTTTTCAGAGACATAGAT (SEQ IDNO: 5032) hCV323071 A/G AAACCAGGATATCAGAACATTTTA (SEQ ID NO: 5033)ACCAGGATATCAGAACATTTTG (SEQ ID NO: 5034)GGTCTTAGGAATTATCTGACATCTT (SEQ ID NO: 5035) hCV3242919 A/CGTGAGTTTTCGTCCCACT (SEQ ID NO: 5036) TGAGTTTTCGTCCCACG (SEQ ID NO: 5037)AAGTGGCCTTTTCTAAGGGGTAGAA (SEQ ID NO: 5038) hCV3242952 A/GGCTATGTGGTTTGAAATTGTTCT (SEQ ID NO: 5039)GCTATGTGGTTTGAAATTGTTCC (SEQ ID NO: 5040)GGAGCACTGGGTCCTAGATGT (SEQ ID NO: 5041) hCV3259235 A/GTCCTCTCCTTGTATCTTCACAT (SEQ ID NO: 5042)TCCTCTCCTTGTATCTTCACAC (SEQ ID NO: 5043)GAGGTAATCAGGTCATGAGGGTATAGT (SEQ ID NO: 5044) hCV3275199 A/GCCATGCAACCAAACCAT (SEQ ID NO: 5045) CCATGCAACCAAACCAC (SEQ ID NO: 5046)CCTCTCATCCCTCTCATCTTT (SEQ ID NO: 5047) hCV334752 C/TCTGTTCCAATATCTCTTTCCCC (SEQ ID NO: 5048)TCTGTTCCAATATCTCTTTCCCT (SEQ ID NO: 5049)GCAAACCATAGCACGCTTATACA (SEQ ID NO: 5050) hCV341736 C/TGTCTGGTGACATAAGGTATTAAATTAAATC (SEQ IDGTCTGGTGACATAAGGTATTAAATTAAATT (SEQ IDAGGTGAATTACATAGGACCCTTTGTGT (SEQ ID NO: 5051) NO: 5052) NO: 5053)hCV342590 C/T AGACAAATTCTCTCATGTCCAC (SEQ ID NO: 5054)AGACAAATTCTCTCATGTCCAT (SEQ ID NO: 5055)TGTTTTTCCAGGAAAAAGATATTC (SEQ ID NO: 5056) hCV361088 A/GCGACTTTCTAGAGGAAATTTAGGT (SEQ ID NO: 5057)CGACTTTCTAGAGGAAATTTAGGC (SEQ ID NO: 5058)CCCAGCAGTCCCGTTGCTTT (SEQ ID NO: 5059) hCV370782 C/TTCTACCCAGGTACTTATCATCC (SEQ ID NO: 5060)TTTCTACCCAGGTACTTATCATCT (SEQ ID NO: 5061)GGATTCACTGTGAAAGAACAGTAT (SEQ ID NO: 5062) hCV435368 T/CGAGGTCTTGAAATACAGGGATT (SEQ ID NO: 5063)GAGGTCTTGAAATACAGGGATC (SEQ ID NO: 5064)TCTTGAGAGGTGTGATCATAACTT (SEQ ID NO: 5065) hCV461035 C/TTGTTTCCCTTATGACAACACG (SEQ ID NO: 5066)CTGTTTCCCTTATGACAACACA (SEQ ID NO: 5067)AGGGTCGGTCAAACTCATGCTATAT (SEQ ID NO: 5068) hCV472000 A/GAAGAATTCACACCCAGGTTTATT (SEQ ID NO: 5069)AGAATTCACACCCAGGTTTATC (SEQ ID NO: 5070)CAACTCCTGAGTTCAAGCAGTCTG (SEQ ID NO: 5071) hCV487868 C/TGCCACAATTTGGAGTTACAGG (SEQ ID NO: 5072)GCCACAATTTGGAGTTACAGA (SEQ ID NO: 5073) CCAATCCAGCCCTCTTGTGTTTG (SEQ IDNO: 5074) hCV491676 T/C GAATTGCAAGTGCTTGTTTTAT (SEQ ID NO: 5075)GAATTGCAAGTGCTTGTTTTAC (SEQ ID NO: 5076)CCGATTCCCCAGTAACAAC (SEQ ID NO: 5077) hCV529178 C/TTGGGTTGGTGGGCAG (SEQ ID NO: 5078) TGGGTTGGTGGGCAA (SEQ ID NO: 5079)GTGGCAGCCAATCTGAGTACT (SEQ ID NO: 5080) hCV529706 C/GGCGAGGACGAAGGGG (SEQ ID NO: 5081) GCGAGGACGAAGGGC (SEQ ID NO: 5082)GGAGGATGAATGGACAGACAA (SEQ ID NO: 5083) hCV529710 C/GCCGACCCGAACTAAAGG (SEQ ID NO: 5084) CCGACCCGAACTAAAGC (SEQ ID NO: 5085)CGCGTTCCCCATGTC (SEQ ID NO: 5086) hCV537525 A/CTCATAGATCCCTACTTGTGCTAA (SEQ ID NO: 5087)TCATAGATCCCTACTTGTGCTAC (SEQ ID NO: 5088)CGCACTGTTCCCTTATCGAGATT (SEQ ID NO: 5089) hCV5478 C/TCGGCTTTCTGGTGGG (SEQ ID NO: 5090) ACGGCTTTCTGGTGGA (SEQ ID NO: 5091)GGCTCCGAGGACGAGA (SEQ ID NO: 5092) hCV549926 C/TACCATGGTCACCCTGG (SEQ ID NO: 5093) CACCATGGTCACCCTGA (SEQ ID NO: 5094)GGACTGAAAGCAATGTGAGAG (SEQ ID NO: 5095) hCV561574 A/GGCCATTTATGTAGCCAAACTGA (SEQ ID NO: 5096)GCCATTTATGTAGCCAAACTGG (SEQ ID NO: 5097)GCAGGTTATAAAGTGTGAGAGATCTGAGTA (SEQ ID NO: 5098) hCV594695 A/TATATCGTGGGTGAGTTCATTTA (SEQ ID NO: 5099)TCGTGGGTGAGTTCATTTT (SEQ ID NO: 5100)GGGTGCTGCTGATGAAATAC (SEQ ID NO: 5101) hCV597227 C/TTTTCTGCAAACTAATTGACAGAAC (SEQ ID NO: 5102)CTTTCTGCAAACTAATTGACAGAAT (SEQ ID NO: 5103)GTCAAGTCCTTTCGGAAATGAGACA (SEQ ID NO: 5104) hCV598677 G/TCCAAGCTGAAAGGCAAG (SEQ ID NO: 5105) CCAAGCTGAAAGGCAAT (SEQ ID NO: 5106)CAGCCAGGGTGGAGAGT (SEQ ID NO: 5107) hCV601946 A/GCTCCATTCTCTTACCCCTCTTAT (SEQ ID NO: 5108)TCCATTCTCTTACCCCTCTTAC (SEQ ID NO: 5109) TTGGGGATGGACTCAAGATGTGT (SEQ IDNO: 5110) hCV601961 A/G CCATTAATTATGAGTGCTCTTACCTAAA (SEQ IDCCATTAATTATGAGTGCTCTTACCTAAG (SEQ ID CCAACCACTCTGGTAGACGTGTAA (SEQ IDNO: 5111) NO: 5112) NO: 5113) hCV601962 A/GAGCATAGAGGACTTCCTGTTT (SEQ ID NO: 5114)AGCATAGAGGACTTCCTGTTC (SEQ ID NO: 5115) GTGCTGGGATTACAGGCAAGAG (SEQ IDNO: 5116) hCV610861 C/T TGGTGCTTGTTAAAATTTGCTG (SEQ ID NO: 5117)GTGGTGCTTGTTAAAATTTGCTA (SEQ ID NO: 5118)CTAAATCAGGTTTATTTGCCATGGAAGAGA (SEQ ID NO: 5119) hCV621313 C/TTCCATGTGTCTGCTACCTC (SEQ ID NO: 5120)TCCATGTGTCTGCTACCTT (SEQ ID NO: 5121)CTCTTTCCCGGCATACCTGAAT (SEQ ID NO: 5122) hCV7425232 C/TTCAAAATTATTTCTTGCTACAGG (SEQ ID NO: 5123)GTCAAAATTATTTCTTGCTACAGA (SEQ ID NO: 5124)TCCTCCAGCCTCTCATTC (SEQ ID NO: 5125) hCV7435390 A/GGTGGCCAGGGAAACAT (SEQ ID NO: 5126) GTGGCCAGGGAAACAC (SEQ ID NO: 5127)CCATGGCGAAGCAAATAT (SEQ ID NO: 5128) hCV7441704 A/GCCAACCGAGATCAGATTGA (SEQ ID NO: 5129)CAACCGAGATCAGATTGG (SEQ ID NO: 5130)TGATGCTGATTGTGGATGATA (SEQ ID NO: 5131) hCV7442005 A/GACTTAACACTACTGAACTGTACATTT (SEQ IDACTTAACACTACTGAACTGTACATTC (SEQ ID NO: 5133)CACACACGCCCCTAAACAATAGAT (SEQ ID NO: 5132) NO: 5134) hCV7442014 C/AAGCAAAACCTTACAAATGTGAC (SEQ ID NO: 5135)AGCAAAACCTTACAAATGTGAA (SEQ ID NO: 5136)TTACCACATTCATTGCATTTG (SEQ ID NO: 5137) hCV7443062 T/CGGAGCAGGATGGTGAT (SEQ ID NO: 5138) GGAGCAGGATGGTGAC (SEQ ID NO: 5139)GGAAATATCTCGTTCTTGTTCTCT (SEQ ID NO: 5140) hCV7451269 A/GCTTCCACTCAGCTTCTTGT (SEQ ID NO: 5141)TTCCACTCAGCTTCTTGC (SEQ ID NO: 5142)GTAACGGGAGCCCCTACAC (SEQ ID NO: 5143) hCV7475492 C/TCCAGACTTACCGATGTAGAC (SEQ ID NO: 5144)CCAGACTTACCGATGTAGAT (SEQ ID NO: 5145) GAGGGCCGCAGAGGT (SEQ ID NO: 5146)hCV7480314 C/T GCATAGCCAAGGACTCCAC (SEQ ID NO: 5147)GCATAGCCAAGGACTCCAT (SEQ ID NO: 5148) AGGTGACAGGAGTCCCTACAAC (SEQ IDNO: 5149) hCV7490135 C/T GCAGTCCTGAACAAAGTAGATG (SEQ ID NO: 5150)CGCAGTCCTGAACAAAGTAGATA (SEQ ID NO: 5151)CGTGCATGTTTTGAAAAATGTA (SEQ ID NO: 5152) hCV7494810 C/GCCCGAGCGGACAGTG (SEQ ID NO: 5153) CCCGAGCGGACAGTC (SEQ ID NO: 5154)CAACTGCTGGCAGAATCTTC (SEQ ID NO: 5155) hCV7499212 C/TGTGATGGTAGACACCTGGG (SEQ ID NO: 5156)TGTGATGGTAGACACCTGGA (SEQ ID NO: 5157)GGCTGCACGGACTCTTC (SEQ ID NO: 5158) hCV7501549 C/TTCAGTTGTTGTGGGCTG (SEQ ID NO: 5159) CTCAGTTGTTGTGGGCTA (SEQ ID NO: 5160)GCCCACCTGCAAGGAATAGAG (SEQ ID NO: 5161) hCV7504854 A/GTCTGGTGCGTAGAATTCCT (SEQ ID NO: 5162)TGGTGCGTAGAATTCCC (SEQ ID NO: 5163) ACAGCAGCAACGATCTCA (SEQ ID NO: 5164)hCV7514870 A/C GAGCAGCAGGTTTGAGGT (SEQ ID NO: 5165)GCAGCAGGTTTGAGGG (SEQ ID NO: 5166)ACACCACCTGAACGTCTCTT (SEQ ID NO: 5167) hCV7514879 A/GGGCTGAACCCCGTCCT (SEQ ID NO: 5168) GCTGAACCCCGTCCC (SEQ ID NO: 5169)CTTTTTCCTGCATCCTGTCT (SEQ ID NO: 5170) hCV7537517 C/GCAGACCCCATTTTACAATAAAGC (SEQ ID NO: 5171)TCAGACCCCATTTTACAATAAAGG (SEQ ID NO: 5172)ACCTGGATTCTATTTTCATCCCATTACATAAGAG (SEQ ID NO: 5173) hCV7577801 C/TCTTTGCTGCTCTGCC (SEQ ID NO: 5174) CCTTTGCTGCTCTGCT (SEQ ID NO: 5175)GGTCTCTGGTATTAAGTGGAAACA (SEQ ID NO: 5176) hCV7618856 C/TGGCTCCCAATGTTAGTGC (SEQ ID NO: 5177)TGGCTCCCAATGTTAGTGT (SEQ ID NO: 5178) GGATTGGTTTGCATTTATTTTAGTA (SEQ IDNO: 5179) hCV783138 A/G CATGCCACCCACTACCA (SEQ ID NO: 5180)ATGCCACCCACTACCG (SEQ ID NO: 5181) GAGCTTTTGCAGCCACTC (SEQ ID NO: 5182)hCV783184 G/T TGCGAGTCAAATCTCAAGAC (SEQ ID NO: 5183)TGCGAGTCAAATCTCAAGAA (SEQ ID NO: 5184)CCTATTCCCGGCACTTCT (SEQ ID NO: 5185) hCV7841642 A/GACCAGCTCCAGGGTGTT (SEQ ID NO: 5186) ACCAGCTCCAGGGTGTC (SEQ ID NO: 5187)TGAAGTTTTGGAATGAGACTGAT (SEQ ID NO: 5188) hCV7900503 C/TCGTCTCCAGGAAAATCATAAC (SEQ ID NO: 5189)CGTCTCCAGGAAAATCATAAT (SEQ ID NO: 5190)TGAGTTATTGCTACTTCAGAATCAT (SEQ ID NO: 5191) hCV7910239 A/GCACTTTGTAACCTAAGAGATGCT (SEQ ID NO: 5192)ACTTTGTAACCTAAGAGATGCC (SEQ ID NO: 5193)GAGAACTCTAGTGAGTCTGTCCTTCAA (SEQ ID NO: 5194) hCV795441 C/GTGTGGGCCAGGACG (SEQ ID NO: 5195) CTGTGGGCCAGGACC (SEQ ID NO: 5196)ACCCACCAGGACCTAAAAG (SEQ ID NO: 5197) hCV795442 A/GCCATTCAATGCAATACGTCA (SEQ ID NO: 5198)CATTCAATGCAATACGTCG (SEQ ID NO: 5199)CCTCTCCTTCCAGAACCAGT (SEQ ID NO: 5200) hCV8072964 A/TCCTGATATCCTTGTTCATCAT (SEQ ID NO: 5201)CCTGATATCCTTGTTCATCAA (SEQ ID NO: 5202)TGTTACGGCTGCTATAATGTGT (SEQ ID NO: 5203) hCV8157049 C/TAGAAGCTGTGTGTCTGGC (SEQ ID NO: 5204)CAGAAGCTGTGTGTCTGGT (SEQ ID NO: 5205)TGGGTAGATGTGGAATCAATAC (SEQ ID NO: 5206) hCV818008 C/TGCGAGGTGAGCCCG (SEQ ID NO: 5207) AGCGAGGTGAGCCCA (SEQ ID NO: 5208)GGGATTATCCCAGGAAAGAC (SEQ ID NO: 5209) hCV8369472 A/GCTTGACTGAAAAGTCTGGTCA (SEQ ID NO: 5210)TTGACTGAAAAGTCTGGTCG (SEQ ID NO: 5211) GTTTCATGGAGGGCTCAGAACT (SEQ IDNO: 5212) hCV8379452 C/T TGATTGCTCTCCTTTGCC (SEQ ID NO: 5213)GTGATTGCTCTCCTTTGCT (SEQ ID NO: 5214) CCACCTGTATCTGCCATTTCTCT (SEQ IDNO: 5215) hCV8420416 C/T CATTATGAGGGTTACAAGAATACTCC (SEQ IDACATTATGAGGGTTACAAGAATACTCT (SEQ ID GGGAAACTCACTTCTGTAGGTAA (SEQ IDNO: 5216) NO: 5217) NO: 5218) hCV8687255 C/TCCTGCTTCAGAGGCTGAC (SEQ ID NO: 5219)CCTGCTTCAGAGGCTGAT (SEQ ID NO: 5220) CCTCTTCTGGCCTTTCCATACAAT (SEQ IDNO: 5221) hCV8696050 A/G GTGCCACGGTCAGGT (SEQ ID NO: 5222)TGCCACGGTCAGGC (SEQ ID NO: 5223) GTGCAACCACCACTTGTCTTTAGTT (SEQ IDNO: 5224) hCV8696079 G/T CAACCTCAGTGGAAAGATGC (SEQ ID NO: 5225)TCAACCTCAGTGGAAAGATGA (SEQ ID NO: 5226)GCCCATGTGCAAAGGTCTCA (SEQ ID NO: 5227) hCV8705506 C/GCCACTTCGGGTTCCTC (SEQ ID NO: 5228) CCACTTCGGGTTCCTG (SEQ ID NO: 5229)CCCTGGCTTCAACATGA (SEQ ID NO: 5230) hCV8708473 A/GGCAACAGGACACCTGAA (SEQ ID NO: 5231) GCAACAGGACACCTGAG (SEQ ID NO: 5232)GAGTGACAGGAGGCTGCTTA (SEQ ID NO: 5233) hCV8709053 A/GGCCCAGATACCCCAAAA (SEQ ID NO: 5234) GCCCAGATACCCCAAAG (SEQ ID NO: 5235)GCCCAGCCTGCGTAGA (SEQ ID NO: 5236) hCV8718197 A/GCCTCTGAGGCCTGAGAAA (SEQ ID NO: 5237)CCTCTGAGGCCTGAGAAG (SEQ ID NO: 5238)GTCCTGATTCCTCATTTCTTTC (SEQ ID NO: 5239) hCV8722613 C/TCCTGGGGCAGGTACAG (SEQ ID NO: 5240) CCTGGGGCAGGTACAA (SEQ ID NO: 5241)CCATCCACTGCTTGAAAAG (SEQ ID NO: 5242) hCV8726337 A/GCACATTCACGGTCACCTT (SEQ ID NO: 5243)CACATTCACGGTCACCTC (SEQ ID NO: 5244) CATTGCCCGAGCTCAA (SEQ ID NO: 5245)hCV8737990 C/T GTCCTTGCAAGTATCCG (SEQ ID NO: 5246)GGTCCTTGCAAGTATCCA (SEQ ID NO: 5247)GCACTACAGCTGAGTCCTTTTC (SEQ ID NO: 5248) hCV8784787 A/CACTTCTGGGGCTTAGGAA (SEQ ID NO: 5249)ACTTCTGGGGCTTAGGAC (SEQ ID NO: 5250)TTCACCGGGAACTCTTGT (SEQ ID NO: 5251) hCV8785824 A/CATTTACAGAAGCTGCAAGAACT (SEQ ID NO: 5252)ACAGAAGCTGCAAGAACG (SEQ ID NO: 5253)CATTTTCTGTTTCTGGATCTGGCAGTAG (SEQ ID NO: 5254) hCV8785827 A/GAGCAAGAACCAGTGATAGGTT (SEQ ID NO: 5255)GCAAGAACCAGTGATAGGTC (SEQ ID NO: 5256)CCTGTTGGCATGCTTGATGATG (SEQ ID NO: 5257) hCV8804621 A/GAGGTTTCTTGGAGGAAGAGAT (SEQ ID NO: 5258)AGGTTTCTTGGAGGAAGAGAC (SEQ ID NO: 5259)GCACTGCACCCAGTGAG (SEQ ID NO: 5260) hCV8804684 A/TTGTGTATATCCACGGCATTAT (SEQ ID NO: 5261)TGTGTATATCCACGGCATTAA (SEQ ID NO: 5262)TGCCCTCACCCAATATTC (SEQ ID NO: 5263) hCV881283 C/GTCAGACACACAGGACACATG (SEQ ID NO: 5264)TTCAGACACACAGGACACATC (SEQ ID NO: 5265)CCCTTCTGCTCCCAGAAC (SEQ ID NO: 5266) hCV8823713 C/TCCGTTATAATCGAAGGGACAC (SEQ ID NO: 5267)TCCGTTATAATCGAAGGGACAT (SEQ ID NO: 5268)GCTTCTCCACTTTCTCACATCAGT (SEQ ID NO: 5269) hCV8824241 G/AAACAGAAAACGAAGTGATCATC (SEQ ID NO: 5270)TAACAGAAAACGAAGTGATCATT (SEQ ID NO: 5271)AGTTCAAGACGGGTCATATTC (SEQ ID NO: 5272) hCV8824244 C/TCCTGTTGACTGACTCATAGGG (SEQ ID NO: 5273)TCCTGTTGACTGACTCATAGGA (SEQ ID NO: 5274)TTGGCCACATGTTCTATCTCTA (SEQ ID NO: 5275) hCV8824248 A/GAAAGCATAGGATGGGGACA (SEQ ID NO: 5276)AGCATAGGATGGGGACG (SEQ ID NO: 5277) CCTGGGTGACAGAGTGAGATTT (SEQ IDNO: 5278) hCV8824394 G/T GTGAGTGTGATTTTGCTCAAC (SEQ ID NO: 5279)TGTGAGTGTGATTTTGCTCAAA (SEQ ID NO: 5280) CCCAAACCCCCAGAGAATAAGT (SEQ IDNO: 5281) hCV8824424 A/G CATGGTGACCCCACATT (SEQ ID NO: 5282)CATGGTGACCCCACATC (SEQ ID NO: 5283) CCCACACAGCATGCTTTCTGAAT (SEQ IDNO: 5284) hCV8824425 A/C GTTGGGATAGGCTTGTTTTGT (SEQ ID NO: 5285)TTGGGATAGGCTTGTTTTGG (SEQ ID NO: 5286) GCCTCCCTGTGAACAAACTAAAGT (SEQ IDNO: 5287) hCV8824453 G/T TCCCTGAGGTGCTGAAG (SEQ ID NO: 5288)TCCCTGAGGTGCTGAAT (SEQ ID NO: 5289) GGCTGGTTCTGGCTTCTTTTATCTC (SEQ IDNO: 5290) hCV8848630 G/T CATCTTCATCATCAAGGGAG (SEQ ID NO: 5291)CATCTTCATCATCAAGGGAT (SEQ ID NO: 5292)TGTTTTCCTCCCTCAGATATCT (SEQ ID NO: 5293) hCV8851047 T/CCCTCAAAGGAAAAGGCTT (SEQ ID NO: 5294)CCTCAAAGGAAAAGGCTC (SEQ ID NO: 5295)GCGGACCATGTGTCAACT (SEQ ID NO: 5296) hCV8851065 C/GCCCCGCAGAGAATTACC (SEQ ID NO: 5297) CCCCGCAGAGAATTACG (SEQ ID NO: 5298)ACGTCGCTGTCGAAGC (SEQ ID NO: 5299) hCV8851085 A/GGCTCGTAGTTGTGTCTGCAT (SEQ ID NO: 5300)GCTCGTAGTTGTGTCTGCAC (SEQ ID NO: 5301)CGCTTCCTGGAGAGATACAT (SEQ ID NO: 5302) hCV8851095 C/TCTCCACTTGGCAGG (SEQ ID NO: 5303) GCTCCACTTGGCAGA (SEQ ID NO: 5304)CACCAACCTGATCCGTAATG (SEQ ID NO: 5305) hCV8881160 C/TTCCTAGAACATACAACAGTTTTAGC (SEQ ID NO: 5306)TCCTAGAACATACAACAGTTTTAGT (SEQ ID NO: 5307)GTGCCTAGCAGATGCCCAATAAATA (SEQ ID NO: 5308) hCV8881161 A/GGAGAAAGTCCTCTATGAACTGATAA (SEQ ID NO: 5309)GAGAAAGTCCTCTATGAACTGATAG (SEQ ID NO: 5310)CCCCGTCTTTCTTATATGAAGGGTAGAA (SEQ ID NO: 5311) hCV8881164 C/TAGAACACAAAATTTCTGTGATACAC (SEQ ID NO: 5312)AAGAACACAAAATTTCTGTGATACAT (SEQ ID NO: 5313)GATCCTCCCGGGCTCAAGT (SEQ ID NO: 5314) hCV8888179 C/TGCCCTCTGCACACCTTC (SEQ ID NO: 5315) GCCCTCTGCACACCTTT (SEQ ID NO: 5316)GGTAGGAGGATCTGCAGTTGT (SEQ ID NO: 5317) hCV8892418 A/GGAGACCAGTCTGACTTACACT (SEQ ID NO: 5318)AGACCAGTCTGACTTACACC (SEQ ID NO: 5319)GCCCGGCCTTCCTAGTATT (SEQ ID NO: 5320) hCV8895373 A/GAGGACTTCCGTGTCTT (SEQ ID NO: 5321) AGGACTTCCGTGTCTC (SEQ ID NO: 5322)ACAGATGCCAGCAATACAGA (SEQ ID NO: 5323) hCV8901525 G/ACAGCTCACGCAGCG (SEQ ID NO: 5324) TCAGCTCACGCAGCA (SEQ ID NO: 5325)CTTGTTGGAGTGTGTGAATAAGA (SEQ ID NO: 5326) hCV8921288 C/ACCGCAGAGGTGTGGG (SEQ ID NO: 5327) CCGCAGAGGTGTGGT (SEQ ID NO: 5328)CATTTTGCGGTGGAAATG (SEQ ID NO: 5329) hCV8936042 C/TACGAGAATCTTCTCCTACACG (SEQ ID NO: 5330)ACGAGAATCTTCTCCTACACA (SEQ ID NO: 5331) GTGTGACCCACTCTTGAAAGACAT (SEQ IDNO: 5332) hCV904973 C/T TCCTCCGCGATGCCGATGACCTGCAGAATC (SEQ IDTCCTCCGCGATGCCGATGACCTGCAGAATT (SEQ ID TCGCGGGCCCCGGCCTGGTACA (SEQ IDNO: 5333) NO: 5334) NO: 5335) hCV904974 C/TGCCGGCACTCTCTTCC (SEQ ID NO: 5336) GCCGGCACTCTCTTCT (SEQ ID NO: 5337)CAGAGGGACAAGCAGATGT (SEQ ID NO: 5338) hCV9055799 C/GACAGATCCATTTCATCTAGGTC (SEQ ID NO: 5339)ACAGATCCATTTCATCTAGGTG (SEQ ID NO: 5340)GGCTCTGGGAATTTCACAT (SEQ ID NO: 5341) hCV9077561 G/AAGAAGGTGGGATCCAAAC (SEQ ID NO: 5342)AGAAGGTGGGATCCAAAT (SEQ ID NO: 5343)AGAAACCATCATGCTGAGGT (SEQ ID NO: 5344) hCV922535 A/GAAACCAAGACTCTGGCAAAT (SEQ ID NO: 5345)AACCAAGACTCTGGCAAAC (SEQ ID NO: 5346)TTCCCAGCTGACCCAGTTCT (SEQ ID NO: 5347) hCV9326822 C/TCTCGGGACCAGTCCAG (SEQ ID NO: 5348) CTCGGGACCAGTCCAA (SEQ ID NO: 5349)CCGACAGCCGAGGAGA (SEQ ID NO: 5350) hCV9494470 G/TAGGGATCCGCAAAGC (SEQ ID NO: 5351) CAGGGATCCGCAAAGA (SEQ ID NO: 5352)TCTTTCTGCCAGGTACATCA (SEQ ID NO: 5353) hCV9506149 A/TCTGCTGGCCGTCCT (SEQ ID NO: 5354) TGCTGGCCGTCCA (SEQ ID NO: 5355)ACTCACGCTTGCTTTGACT (SEQ ID NO: 5356) hCV9528413 G/CGTCGTCCTGCTGATTTCC (SEQ ID NO: 5357) TCGTCCTGCTGATTTCG (SEQ ID NO: 5358)GGAAGGCCGGGATACTC (SEQ ID NO: 5359) hCV9549398 A/GTCCTGCACTGTATGATATATGTGA (SEQ ID NO: 5360)CCTGCACTGTATGATATATGTGG (SEQ ID NO: 5361)CAAAAGTCAACAAATGTGTTTACATA (SEQ ID NO: 5362) hCV9581635 C/GCTGGAGTAATAACAGGAATACTGTC (SEQ ID NO: 5363)CTGGAGTAATAACAGGAATACTGTG (SEQ ID NO: 5364)CACTGCAAGTCTGTCTCACATAGGA (SEQ ID NO: 5365) hCV9588862 C/TAGCTGAGGGAACAATATTAACG (SEQ ID NO: 5366)AAGCTGAGGGAACAATATTAACA (SEQ ID NO: 5367)GCCACCTGGGAAAGGCTAAAT (SEQ ID NO: 5368) hCV9589513 C/GGTGATGGATGCCACTGTC (SEQ ID NO: 5369) TGATGGATGCCACTGTG (SEQ ID NO: 5370)CCTGAGTTTTTTGACACATCTCT (SEQ ID NO: 5371) hCV9596963 A/GTGCCCCCAGCCAGAA (SEQ ID NO: 5372) TGCCCCCAGCCAGAG (SEQ ID NO: 5373)GGCCCTCCAGGATCTG (SEQ ID NO: 5374) hCV9604851 A/GCCGCCTTGCAGATGAT (SEQ ID NO: 5375) CCGCCTTGCAGATGAC (SEQ ID NO: 5376)GGAGCTGGCCATTAGAATC (SEQ ID NO: 5377) hCV997884 A/GCGGTGTCAGCACCTTTGA (SEQ ID NO: 5378) GGTGTCAGCACCTTTGG (SEQ ID NO: 5379)CCCCCAAGCAACCACA (SEQ ID NO: 5380) hDV68873046 A/TTGGGATGAATTCTTCAATGATAAGAT (SEQ IDTGGGATGAATTCTTCAATGATAAGAA (SEQ ID NO: 5382)TGCTGGTGCCTGTACCT (SEQ ID NO: 5383) NO: 5381) hDV70661573 A/TCCTGTGGTCGCCATCAA (SEQ ID NO: 5384) CCTGTGGTCGCCATCAT (SEQ ID NO: 5385)TTCAGGCTGTTCAGACAGTAGTG (SEQ ID NO: 5386) hDV70715669 A/TGATTTGATTGGAGTCCAGGAAA (SEQ ID NO: 5387)GATTTGATTGGAGTCCAGGAAT (SEQ ID NO: 5388)CTGCTCCCAGCTCCAGTTTATC (SEQ ID NO: 5389) hDV70751699 A/TGGGCCATTTCTGCTGTA (SEQ ID NO: 5390) GGGCCATTTCTGCTGTT (SEQ ID NO: 5391)CCAGACCCCAACTCAGTAGTAGAT (SEQ ID NO: 5392) hDV70751704 A/TCTCTTCTCGCCCCAGA (SEQ ID NO: 5393) CTCTTCTCGCCCCAGT (SEQ ID NO: 5394)AGAACACAGGCTTACACGCTTTTC (SEQ ID NO: 5395) hDV70751706 C/GGTGGCTTCGTCATGTAGG (SEQ ID NO: 5396)GTGGCTTCGTCATGTAGC (SEQ ID NO: 5397) CGTGTAAGCCTGTGTTCTTTCTGAA (SEQ IDNO: 5398) hDV70797856 C/T AAAGGTGCAAAACATCCAATTC (SEQ ID NO: 5399)GAAAGGTGCAAAACATCCAATTT (SEQ ID NO: 5400)CCCAGGCTAGTCTTGAACTTCT (SEQ ID NO: 5401) hDV70938014 A/GACTTTCGTCCTCTTCATACCTA (SEQ ID NO: 5402)CTTTCGTCCTCTTCATACCTG (SEQ ID NO: 5403) GGGGTTCACTCTTGGTACCTTCTT (SEQ IDNO: 5404) hDV70973697 C/T GCCATGAGACATAACATGCTTC (SEQ ID NO: 5405)GCCATGAGACATAACATGCTTT (SEQ ID NO: 5406)CGGCTTAAGGCAGAACATTTAGAGA (SEQ ID NO: 5407) hDV70977122 A/GGGACAGTGGTGCTAGTAGTT (SEQ ID NO: 5408)GGACAGTGGTGCTAGTAGTC (SEQ ID NO: 5409) ACCCTGACCACTCTGGAACATAC (SEQ IDNO: 5410) hDV76976592 A/G CTTCCAGAAAGCTCTGGGA (SEQ ID NO: 5411)TCCAGAAAGCTCTGGGG (SEQ ID NO: 5412) CAGGTCAACAGAGCCTACGAATAAT (SEQ IDNO: 5413)

TABLE 6 Interrogated SNP Interrogated (hCV #) SNP (rs #) LD SNP (hCV #)LD SNP (rs #) Power Threshold r² r² hCV10048483 rs2145270 hCV10048484rs1000972 0.51 0.9 0.9242 hCV10048483 rs2145270 hCV10048501 rs9790120.51 0.9 0.9242 hCV10048483 rs2145270 hCV2513354 rs6054427 0.51 0.9 1hCV1026586 rs673548 hCV11168489 rs2678379 0.51 0.9 1 hCV1026586 rs673548hCV11168524 rs6544366 0.51 0.9 0.9441 hCV1026586 rs673548 hCV11168530rs6728178 0.51 0.9 0.9441 hCV1026586 rs673548 hCV260164 rs6754295 0.510.9 0.9441 hCV1026586 rs673548 hCV30847428 rs11902417 0.51 0.9 0.9441hCV1026586 rs673548 hCV3216558 rs676210 0.51 0.9 1 hCV1026586 rs673548hCV7615376 rs1042034 0.51 0.9 0.9709 hCV11170747 rs2066853 hCV15956280rs2237297 0.51 0.9 1 hCV11170747 rs2066853 hCV16163703 rs2074113 0.510.9 1 hCV11170747 rs2066853 hCV29793055 rs10274243 0.51 0.9 1hCV11231076 rs4857855 hCV487869 rs4431128 0.51 0.9 1 hCV11398434rs1812457 hCV11398437 rs1817367 0.51 0.515519235 1 hCV11398434 rs1812457hCV11675962 rs10746481 0.51 0.515519235 0.9381 hCV11398434 rs1812457hCV1188731 rs4908514 0.51 0.515519235 0.8094 hCV11398434 rs1812457hCV1188735 rs10864366 0.51 0.515519235 0.7979 hCV11398434 rs1812457hCV15882429 rs2289732 0.51 0.515519235 0.5975 hCV11398434 rs1812457hCV15932991 rs2781067 0.51 0.515519235 0.5861 hCV11398434 rs1812457hCV27157507 rs6664000 0.51 0.515519235 0.7979 hCV11398434 rs1812457hCV27157524 rs6577531 0.51 0.515519235 0.7539 hCV11398434 rs1812457hCV2741759 rs11121179 0.51 0.515519235 0.5747 hCV11398434 rs1812457hCV27884601 rs4908776 0.51 0.515519235 0.8089 hCV11398434 rs1812457hCV27958354 rs4908762 0.51 0.515519235 0.8759 hCV11398434 rs1812457hCV28023091 rs4908773 0.51 0.515519235 0.7979 hCV11398434 rs1812457hCV29368919 rs4908513 0.51 0.515519235 0.8094 hCV11398434 rs1812457hCV2943451 rs902355 0.51 0.515519235 0.6736 hCV11398434 rs1812457hCV2943853 rs301793 0.51 0.515519235 0.5975 hCV11398434 rs1812457hCV2966436 rs11121174 0.51 0.515519235 0.5975 hCV11398434 rs1812457hCV2966437 rs11580417 0.51 0.515519235 0.5975 hCV11398434 rs1812457hCV2966441 rs6684863 0.51 0.515519235 0.5975 hCV11398434 rs1812457hCV2966444 rs11121171 0.51 0.515519235 0.6417 hCV11398434 rs1812457hCV29819064 rs6698079 0.51 0.515519235 1 hCV11398434 rs1812457hCV2987250 rs301810 0.51 0.515519235 0.7861 hCV11398434 rs1812457hCV29873524 rs7533113 0.51 0.515519235 0.8094 hCV11398434 rs1812457hCV29873526 rs6697997 0.51 0.515519235 0.8824 hCV11398434 rs1812457hCV29945430 rs7517436 0.51 0.515519235 0.7979 hCV11398434 rs1812457hCV30035535 rs7518204 0.51 0.515519235 0.8087 hCV11398434 rs1812457hCV30125699 rs4581300 0.51 0.515519235 0.8759 hCV11398434 rs1812457hCV30143725 rs6690050 0.51 0.515519235 0.9381 hCV11398434 rs1812457hCV30467730 rs6702457 0.51 0.515519235 0.9381 hCV11398434 rs1812457hCV3086930 rs6658881 0.51 0.515519235 0.9345 hCV11398434 rs1812457hCV3086932 rs7533442 0.51 0.515519235 0.9345 hCV11398434 rs1812457hCV3086950 rs4908771 0.51 0.515519235 0.9381 hCV11398434 rs1812457hCV3086961 rs6703577 0.51 0.515519235 1 hCV11398434 rs1812457 hCV3086971rs6679948 0.51 0.515519235 1 hCV11398434 rs1812457 hCV3086972 rs66883290.51 0.515519235 1 hCV11398434 rs1812457 hCV3086998 rs7530863 0.510.515519235 0.8759 hCV11398434 rs1812457 hCV3087000 rs1463055 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV3087003 rs6577500 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV3087015 rs11121198 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV3087016 rs2297867 0.510.515519235 0.8759 hCV11398434 rs1812457 hCV32055284 rs12079653 0.510.515519235 0.6858 hCV11398434 rs1812457 hCV32055470 rs6577506 0.510.515519235 1 hCV11398434 rs1812457 hCV32055474 rs10864359 0.510.515519235 1 hCV11398434 rs1812457 hCV32055477 rs10779705 0.510.515519235 1 hCV11398434 rs1812457 hCV32055527 rs10864364 0.510.515519235 0.7979 hCV11398434 rs1812457 hCV32055548 rs11121197 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV32055579 rs6577522 0.510.515519235 0.8092 hCV11398434 rs1812457 hCV32055595 rs6577524 0.510.515519235 0.8094 hCV11398434 rs1812457 hCV32055596 rs6577525 0.510.515519235 0.7979 hCV11398434 rs1812457 hCV32055625 rs6678590 0.510.515519235 0.7684 hCV11398434 rs1812457 hCV32055637 rs6577532 0.510.515519235 0.7394 hCV11398434 rs1812457 hCV32055662 rs6677249 0.510.515519235 0.5758 hCV11398434 rs1812457 hCV32055677 rs10864355 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV529178 rs301811 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV529182 rs301800 0.510.515519235 0.6217 hCV11398434 rs1812457 hCV597227 rs301809 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV597229 rs301785 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV877241 rs301788 0.510.515519235 0.5747 hCV11398434 rs1812457 hCV8823713 rs1472228 0.510.515519235 0.7979 hCV11398434 rs1812457 hCV8824288 rs910582 0.510.515519235 0.8824 hCV11398434 rs1812457 hCV8824394 rs1443929 0.510.515519235 0.5747 hCV11398434 rs1812457 hCV8824424 rs1058790 0.510.515519235 0.6417 hCV11398434 rs1812457 hCV8824425 rs1058791 0.510.515519235 0.62 hCV11398434 rs1812457 hCV8881145 rs1038008 0.510.515519235 1 hCV11398434 rs1812457 hCV8881146 rs1463054 0.510.515519235 1 hCV11398434 rs1812457 hCV8881157 rs1535158 0.510.515519235 1 hCV11398434 rs1812457 hCV8881161 rs926951 0.51 0.5155192350.8759 hCV11398437 rs1817367 hCV11398434 rs1812457 0.51 0.883097369 1hCV11398437 rs1817367 hCV11675962 rs10746481 0.51 0.883097369 0.9276hCV11398437 rs1817367 hCV27958354 rs4908762 0.51 0.883097369 0.8987hCV11398437 rs1817367 hCV29819064 rs6698079 0.51 0.883097369 1hCV11398437 rs1817367 hCV30125699 rs4581300 0.51 0.883097369 0.8936hCV11398437 rs1817367 hCV30143725 rs6690050 0.51 0.883097369 0.9276hCV11398437 rs1817367 hCV30467730 rs6702457 0.51 0.883097369 0.9276hCV11398437 rs1817367 hCV3086950 rs4908771 0.51 0.883097369 0.9276hCV11398437 rs1817367 hCV3086961 rs6703577 0.51 0.883097369 0.9642hCV11398437 rs1817367 hCV3086971 rs6679948 0.51 0.883097369 1hCV11398437 rs1817367 hCV3086972 rs6688329 0.51 0.883097369 1hCV11398437 rs1817367 hCV3086998 rs7530863 0.51 0.883097369 0.8987hCV11398437 rs1817367 hCV32055470 rs6577506 0.51 0.883097369 0.9642hCV11398437 rs1817367 hCV32055474 rs10864359 0.51 0.883097369 0.8987hCV11398437 rs1817367 hCV32055477 rs10779705 0.51 0.883097369 1hCV11398437 rs1817367 hCV8881145 rs1038008 0.51 0.883097369 1hCV11398437 rs1817367 hCV8881146 rs1463054 0.51 0.883097369 1hCV11398437 rs1817367 hCV8881157 rs1535158 0.51 0.883097369 1hCV11398437 rs1817367 hCV8881161 rs926951 0.51 0.883097369 0.8987hCV11438723 rs1877273 hCV15830836 rs2859641 0.51 0.9 1 hCV11438723rs1877273 hCV15868592 rs2941949 0.51 0.9 0.9549 hCV11438723 rs1877273hCV15912032 rs2667617 0.51 0.9 0.9549 hCV11438723 rs1877273 hCV15912048rs2667611 0.51 0.9 0.9549 hCV11438723 rs1877273 hCV15912085 rs26676320.51 0.9 1 hCV11438723 rs1877273 hCV15912105 rs2667623 0.51 0.9 1hCV11438723 rs1877273 hCV1592156 rs2738745 0.51 0.9 0.9549 hCV11438723rs1877273 hCV1592157 rs2667614 0.51 0.9 1 hCV11438723 rs1877273hCV1592158 rs3106331 0.51 0.9 1 hCV11438723 rs1877273 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0.9 0.9608 hCV1323634rs287475 hCV615776 rs287476 0.51 0.9 0.9166 hCV1323634 rs287475hCV615780 rs287439 0.51 0.9 0.9166 hCV1323669 rs287354 hCV1323632rs287479 0.51 0.9 0.9244 hCV1323669 rs287354 hCV1323635 rs287474 0.510.9 0.9244 hCV1323669 rs287354 hCV1323659 rs287360 0.51 0.9 0.9234hCV1323669 rs287354 hCV1323670 rs167000 0.51 0.9 0.9407 hCV1323669rs287354 hCV1323673 rs287352 0.51 0.9 0.98 hCV1323669 rs287354hCV1323678 rs287350 0.51 0.9 0.9796 hCV1323669 rs287354 hCV1323680rs12585011 0.51 0.9 0.9617 hCV1323669 rs287354 hCV1323684 rs287347 0.510.9 0.9617 hCV1323669 rs287354 hCV1323686 rs2039578 0.51 0.9 0.98hCV1323669 rs287354 hCV1323696 rs11842785 0.51 0.9 0.9609 hCV1323669rs287354 hCV1323700 rs6562535 0.51 0.9 0.9568 hCV1323669 rs287354hCV1323701 rs7330307 0.51 0.9 0.96 hCV1323669 rs287354 hCV1323702rs7329795 0.51 0.9 0.96 hCV1323669 rs287354 hCV1323703 rs17641312 0.510.9 0.9395 hCV1323669 rs287354 hCV1323704 rs8002457 0.51 0.9 0.9401hCV1323669 rs287354 hCV32085644 rs12585431 0.51 0.9 0.9617 hCV1323669rs287354 hCV32085645 rs11842784 0.51 0.9 0.9609 hCV1323669 rs287354hCV615776 rs287476 0.51 0.9 0.9408 hCV1323669 rs287354 hCV615780rs287439 0.51 0.9 0.9408 hCV1323669 rs287354 hCV7597674 rs287356 0.510.9 0.98 hCV1345898 rs2230804 hCV11753633 rs7923726 0.51 0.9 1hCV1345898 rs2230804 hCV1345851 rs2270961 0.51 0.9 0.981 hCV1345898rs2230804 hCV1345862 rs6584354 0.51 0.9 0.9619 hCV1345898 rs2230804hCV1345912 rs7909855 0.51 0.9 0.9621 hCV1345898 rs2230804 hCV1858698rs3818411 0.51 0.9 0.981 hCV1345898 rs2230804 hCV25592811 rs4919438 0.510.9 0.981 hCV1345898 rs2230804 hCV29348491 rs7922807 0.51 0.9 0.9619hCV1345898 rs2230804 hCV29348492 rs7079072 0.51 0.9 0.9649 hCV1345898rs2230804 hCV31980317 rs12254005 0.51 0.9 1 hCV1345898 rs2230804hCV31980340 rs12242503 0.51 0.9 0.9619 hCV1345898 rs2230804 hCV31980399rs12269373 0.51 0.9 0.981 hCV1361979 rs25683 hCV11414348 rs13202042 0.510.9 0.9812 hCV1361979 rs25683 hCV1361961 rs3818299 0.51 0.9 0.9812hCV1361979 rs25683 hCV1361978 rs11751480 0.51 0.9 0.9621 hCV1361979rs25683 hCV1361983 rs13194896 0.51 0.9 1 hCV1361979 rs25683 hCV1361988rs3798211 0.51 0.9 0.9628 hCV1361979 rs25683 hCV1362003 rs1440 0.51 0.90.9812 hCV1361979 rs25683 hCV15818677 rs2842970 0.51 0.9 0.9648hCV1361979 rs25683 hCV15818688 rs2842975 0.51 0.9 0.9648 hCV1361979rs25683 hCV15818690 rs2842972 0.51 0.9 0.9807 hCV1361979 rs25683hCV16179956 rs2273828 0.51 0.9 0.9812 hCV1361979 rs25683 hCV16191216rs2295899 0.51 0.9 0.9812 hCV1361979 rs25683 hCV16288760 rs2758311 0.510.9 0.9635 hCV1361979 rs25683 hCV8699839 rs927450 0.51 0.9 0.9812hCV1375141 rs1881420 hCV11167501 rs12619135 0.51 0.9 1 hCV1375141rs1881420 hCV1375138 rs13428329 0.51 0.9 1 hCV1375141 rs1881420hCV1375139 rs4666172 0.51 0.9 0.9054 hCV1375141 rs1881420 hCV1375144rs2278879 0.51 0.9 1 hCV1375141 rs1881420 hCV27505984 rs3820712 0.51 0.90.9054 hCV1375141 rs1881420 hCV27513883 rs3768672 0.51 0.9 1 hCV1375141rs1881420 hCV30109305 rs4666176 0.51 0.9 0.9054 hCV1375141 rs1881420hCV32191953 rs13386033 0.51 0.9 0.9124 hCV1375141 rs1881420 hCV9531551rs1026277 0.51 0.9 1 hCV1463112 rs3763608 hCV11765753 rs3793456 0.510.763750033 0.827 hCV1463112 rs3763608 hCV1463244 rs3793465 0.510.763750033 0.8333 hCV1463112 rs3763608 hCV1463252 rs3793461 0.510.763750033 0.8591 hCV1463112 rs3763608 hCV15761059 rs2309393 0.510.763750033 0.8333 hCV1463112 rs3763608 hCV26566199 rs3793467 0.510.763750033 0.8591 hCV1463112 rs3763608 hCV28008078 rs4745543 0.510.763750033 1 hCV1463112 rs3763608 hCV30586985 rs10126006 0.510.763750033 0.8497 hCV1463112 rs3763608 hCV31363797 rs11145043 0.510.763750033 0.7954 hCV1463112 rs3763608 hCV31363840 rs7875693 0.510.763750033 0.7758 hCV1463112 rs3763608 hCV31363841 rs7849347 0.510.763750033 0.792 hCV1463222 rs4744808 hCV11373123 rs1984003 0.510.343783224 1 hCV1463222 rs4744808 hCV11761245 rs7043149 0.510.343783224 0.3997 hCV1463222 rs4744808 hCV11765727 rs10781379 0.510.343783224 1 hCV1463222 rs4744808 hCV11765729 rs7875659 0.510.343783224 1 hCV1463222 rs4744808 hCV11765753 rs3793456 0.510.343783224 0.7223 hCV1463222 rs4744808 hCV1463101 rs7871596 0.510.343783224 0.4845 hCV1463222 rs4744808 hCV1463112 rs3763608 0.510.343783224 0.5342 hCV1463222 rs4744808 hCV1463185 rs953588 0.510.343783224 0.5193 hCV1463222 rs4744808 hCV1463197 rs6560551 0.510.343783224 0.7657 hCV1463222 rs4744808 hCV1463216 rs4745581 0.510.343783224 1 hCV1463222 rs4744808 hCV1463217 rs4745580 0.51 0.3437832240.7657 hCV1463222 rs4744808 hCV1463218 rs1984004 0.51 0.343783224 1hCV1463222 rs4744808 hCV1463223 rs4744807 0.51 0.343783224 0.7609hCV1463222 rs4744808 hCV1463225 rs4745577 0.51 0.343783224 1 hCV1463222rs4744808 hCV1463226 rs10890 0.51 0.343783224 1 hCV1463222 rs4744808hCV1463229 rs7861997 0.51 0.343783224 0.7996 hCV1463222 rs4744808hCV1463231 rs7870295 0.51 0.343783224 0.7657 hCV1463222 rs4744808hCV1463232 rs9314854 0.51 0.343783224 1 hCV1463222 rs4744808 hCV1463235rs2498430 0.51 0.343783224 0.4988 hCV1463222 rs4744808 hCV1463244rs3793465 0.51 0.343783224 0.6837 hCV1463222 rs4744808 hCV1463247rs3829064 0.51 0.343783224 0.5777 hCV1463222 rs4744808 hCV1463251rs2498434 0.51 0.343783224 0.4995 hCV1463222 rs4744808 hCV1463252rs3793461 0.51 0.343783224 0.6777 hCV1463222 rs4744808 hCV1463256rs2309394 0.51 0.343783224 0.4563 hCV1463222 rs4744808 hCV15761059rs2309393 0.51 0.343783224 0.6837 hCV1463222 rs4744808 hCV15892414rs2498431 0.51 0.343783224 0.4988 hCV1463222 rs4744808 hCV15892430rs2498433 0.51 0.343783224 0.3691 hCV1463222 rs4744808 hCV25609765rs3829062 0.51 0.343783224 0.4563 hCV1463222 rs4744808 hCV26566199rs3793467 0.51 0.343783224 0.6777 hCV1463222 rs4744808 hCV26566299rs10869821 0.51 0.343783224 1 hCV1463222 rs4744808 hCV27517372 rs37934570.51 0.343783224 0.5504 hCV1463222 rs4744808 hCV27996874 rs4745701 0.510.343783224 0.3878 hCV1463222 rs4744808 hCV28008078 rs4745543 0.510.343783224 0.5597 hCV1463222 rs4744808 hCV28035790 rs4744811 0.510.343783224 0.7505 hCV1463222 rs4744808 hCV29861776 rs9411171 0.510.343783224 0.5777 hCV1463222 rs4744808 hCV30586985 rs10126006 0.510.343783224 0.6289 hCV1463222 rs4744808 hCV31363797 rs11145043 0.510.343783224 0.722 hCV1463222 rs4744808 hCV31363840 rs7875693 0.510.343783224 0.6922 hCV1463222 rs4744808 hCV31363841 rs7849347 0.510.343783224 0.7494 hCV1463222 rs4744808 hCV31363869 rs11145070 0.510.343783224 1 hCV1463222 rs4744808 hCV31363888 rs7859021 0.510.343783224 1 hCV1463222 rs4744808 hCV31363984 rs7855905 0.510.343783224 0.6837 hCV1463222 rs4744808 hCV31364141 rs11145460 0.510.343783224 0.3887 hCV1463222 rs4744808 hCV320569 rs9411170 0.510.343783224 0.444 hCV1463222 rs4744808 hCV8785184 rs1411676 0.510.343783224 1 hCV1463222 rs4744808 hCV8785185 rs1411675 0.51 0.3437832241 hCV1463222 rs4744808 hCV9333267 rs1045632 0.51 0.343783224 1hCV1463222 rs4744808 hDV71871695 rs7047274 0.51 0.343783224 0.4858hCV1488444 rs10164405 hCV1488443 rs10409390 0.51 0.9 0.9556 hCV1488444rs10164405 hCV1488445 rs2020362 0.51 0.9 0.9556 hCV1488444 rs10164405hCV1488457 rs1529736 0.51 0.9 0.915 hCV1488444 rs10164405 hCV27115656rs17546075 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV27115659 rs104241690.51 0.9 0.9755 hCV1488444 rs10164405 hCV27115660 rs10423958 0.51 0.90.9556 hCV1488444 rs10164405 hCV27115665 rs17628547 0.51 0.9 0.9556hCV1488444 rs10164405 hCV27115673 rs7351092 0.51 0.9 0.9118 hCV1488444rs10164405 hCV29999392 rs10405722 0.51 0.9 0.9755 hCV1488444 rs10164405hCV30197290 rs10405541 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV30467374rs10402416 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV3057588 rs129771650.51 0.9 0.9514 hCV1488444 rs10164405 hCV3057604 rs17628655 0.51 0.90.9035 hCV1488444 rs10164405 hDV70967049 rs17545436 0.51 0.9 0.9135hCV1488444 rs10164405 hDV70967068 rs17545624 0.51 0.9 0.9278 hCV1488444rs10164405 hDV70967114 rs17545970 0.51 0.9 0.9124 hCV1488444 rs10164405hDV70979159 rs17628152 0.51 0.9 0.9755 hCV1488444 rs10164405 hDV70979177rs17628232 0.51 0.9 0.9755 hCV1488444 rs10164405 hDV75173800 rs176280990.51 0.9 0.9088 hCV1489995 rs4013819 hCV1489958 rs1501572 0.51 0.90.9295 hCV1489995 rs4013819 hCV1489988 rs7036937 0.51 0.9 1 hCV1489995rs4013819 hCV1489991 rs10968723 0.51 0.9 0.9618 hCV1489995 rs4013819hCV1489993 rs2134110 0.51 0.9 1 hCV1489995 rs4013819 hCV1489996rs10120379 0.51 0.9 0.9611 hCV1489995 rs4013819 hCV1490005 rs78483070.51 0.9 0.9425 hCV1489995 rs4013819 hCV27089552 rs7868575 0.51 0.90.9431 hCV1489995 rs4013819 hCV29340958 rs7862374 0.51 0.9 0.9431hCV1489995 rs4013819 hCV31943333 rs12339768 0.51 0.9 0.9648 hCV1489995rs4013819 hCV31943390 rs10968708 0.51 0.9 0.9415 hCV1552894 rs434473hCV12121729 rs10852889 0.51 0.9 1 hCV1552894 rs434473 hCV1552899rs2292353 0.51 0.9 1 hCV1552894 rs434473 hCV1552900 rs1126667 0.51 0.9 1hCV1552894 rs434473 hCV1552901 rs1042356 0.51 0.9 1 hCV1552894 rs434473hCV1552908 rs312466 0.51 0.9 0.9811 hCV1552894 rs434473 hCV15867474rs2070590 0.51 0.9 1 hCV1552894 rs434473 hCV16195939 rs2070589 0.51 0.91 hCV1552894 rs434473 hCV31413421 rs6502998 0.51 0.9 0.9435 hCV1552894rs434473 hCV9277205 rs6502999 0.51 0.9 0.9646 hCV1552900 rs1126667hCV12121729 rs10852889 0.51 0.9 1 hCV1552900 rs1126667 hCV1552894rs434473 0.51 0.9 1 hCV1552900 rs1126667 hCV1552899 rs2292353 0.51 0.9 1hCV1552900 rs1126667 hCV1552901 rs1042356 0.51 0.9 1 hCV1552900rs1126667 hCV1552908 rs312466 0.51 0.9 0.9808 hCV1552900 rs1126667hCV15867474 rs2070590 0.51 0.9 1 hCV1552900 rs1126667 hCV16195939rs2070589 0.51 0.9 1 hCV1552900 rs1126667 hCV31413421 rs6502998 0.51 0.90.9426 hCV1552900 rs1126667 hCV9277205 rs6502999 0.51 0.9 0.9634hCV15758290 rs6716834 hCV1533428 rs2544376 0.51 0.9 0.9765 hCV15758290rs6716834 hCV8822225 rs2544377 0.51 0.9 1 hCV15758290 rs6716834hCV8822233 rs861239 0.51 0.9 1 hCV15758290 rs6716834 hCV95255 rs25443810.51 0.9 0.9776 hCV15758290 rs6716834 hCV95256 rs2544380 0.51 0.9 1hCV15851779 rs2230009 hCV12105879 rs2037962 0.51 0.9 1 hCV15851779rs2230009 hCV15793665 rs3087418 0.51 0.9 1 hCV15851779 rs2230009hCV25471760 rs3087409 0.51 0.9 1 hCV15851779 rs2230009 hCV25921517rs3213197 0.51 0.9 1 hCV15851779 rs2230009 hCV25921527 rs4987239 0.510.9 1 hCV15851779 rs2230009 hCV27829132 rs11574175 0.51 0.9 1hCV15851779 rs2230009 hCV31337210 rs11574400 0.51 0.9 0.9286 hCV15851779rs2230009 hCV31674015 rs11574266 0.51 0.9 1 hCV15851779 rs2230009hCV31674023 rs7829687 0.51 0.9 1 hCV15851779 rs2230009 hCV31674032rs11574260 0.51 0.9 1 hCV15851779 rs2230009 hCV31674034 rs11574259 0.510.9 1 hCV15851779 rs2230009 hCV31674062 rs11574238 0.51 0.9 1hCV15851779 rs2230009 hCV31674064 rs11574235 0.51 0.9 0.9327 hCV15851779rs2230009 hCV31674067 rs11574227 0.51 0.9 1 hCV15851779 rs2230009hCV31674074 rs11574220 0.51 0.9 1 hCV15851779 rs2230009 hCV31674103rs7003607 0.51 0.9 1 hCV15851779 rs2230009 hDV70705670 rs16877715 0.510.9 1 hCV15870728 rs2943245 hCV3033539 rs2663041 0.51 0.9 0.9342hCV15870728 rs2943245 hCV3033560 rs2671694 0.51 0.9 0.9319 hCV15876011rs2228541 hCV1260386 rs8005533 0.51 0.9 1 hCV15876011 rs2228541hCV1260388 rs11160169 0.51 0.9 1 hCV15876011 rs2228541 hCV30012503rs10498639 0.51 0.9 0.9628 hCV15876011 rs2228541 hCV30246438 rs80230230.51 0.9 1 hCV15876011 rs2228541 hCV31536164 rs11627651 0.51 0.9 1hCV15876011 rs2228541 hCV31536166 rs11622970 0.51 0.9 1 hCV15892430rs2498433 hCV11765753 rs3793456 0.51 0.49786513 0.5315 hCV15892430rs2498433 hCV1463101 rs7871596 0.51 0.49786513 0.6974 hCV15892430rs2498433 hCV1463197 rs6560551 0.51 0.49786513 0.5544 hCV15892430rs2498433 hCV1463217 rs4745580 0.51 0.49786513 0.5544 hCV15892430rs2498433 hCV1463223 rs4744807 0.51 0.49786513 0.5544 hCV15892430rs2498433 hCV1463229 rs7861997 0.51 0.49786513 0.5055 hCV15892430rs2498433 hCV1463231 rs7870295 0.51 0.49786513 0.5544 hCV15892430rs2498433 hCV1463235 rs2498430 0.51 0.49786513 0.7645 hCV15892430rs2498433 hCV1463247 rs3829064 0.51 0.49786513 0.7486 hCV15892430rs2498433 hCV1463251 rs2498434 0.51 0.49786513 0.7304 hCV15892430rs2498433 hCV1463252 rs3793461 0.51 0.49786513 0.608 hCV15892430rs2498433 hCV1463256 rs2309394 0.51 0.49786513 0.7999 hCV15892430rs2498433 hCV15892414 rs2498431 0.51 0.49786513 0.7645 hCV15892430rs2498433 hCV25609765 rs3829062 0.51 0.49786513 0.7999 hCV15892430rs2498433 hCV26566199 rs3793467 0.51 0.49786513 0.608 hCV15892430rs2498433 hCV27517372 rs3793457 0.51 0.49786513 0.7181 hCV15892430rs2498433 hCV28008078 rs4745543 0.51 0.49786513 0.5053 hCV15892430rs2498433 hCV28035790 rs4744811 0.51 0.49786513 0.5181 hCV15892430rs2498433 hCV29861776 rs9411171 0.51 0.49786513 0.7486 hCV15892430rs2498433 hCV30586985 rs10126006 0.51 0.49786513 0.5477 hCV15892430rs2498433 hCV31363797 rs11145043 0.51 0.49786513 0.5225 hCV15892430rs2498433 hCV31363840 rs7875693 0.51 0.49786513 0.5159 hCV15892430rs2498433 hCV31363841 rs7849347 0.51 0.49786513 0.556 hCV15892430rs2498433 hCV31363984 rs7855905 0.51 0.49786513 0.5225 hCV15892430rs2498433 hCV320569 rs9411170 0.51 0.49786513 0.7647 hCV15892430rs2498433 hDV71871695 rs7047274 0.51 0.49786513 0.7304 hCV15954277rs2236379 hCV1872594 rs1886050 0.51 0.9 1 hCV15954277 rs2236379hCV27483955 rs3793729 0.51 0.9 0.9075 hCV15954645 rs2954029 hCV11593303rs2980871 0.51 0.9 0.9306 hCV15954645 rs2954029 hCV12004940 rs20018440.51 0.9 0.9655 hCV15954645 rs2954029 hCV15883779 rs2980869 0.51 0.90.9634 hCV15954645 rs2954029 hCV15883790 rs2980875 0.51 0.9 1hCV15954645 rs2954029 hCV15954624 rs2954022 0.51 0.9 1 hCV15954645rs2954029 hCV26372062 rs2980856 0.51 0.9 0.9634 hCV15954645 rs2954029hCV26372064 rs2980855 0.51 0.9 0.9655 hCV15954645 rs2954029 hCV26372065rs2980854 0.51 0.9 0.9655 hCV15954645 rs2954029 hCV26372066 rs29808530.51 0.9 0.9634 hCV15954645 rs2954029 hCV26372069 rs2980882 0.51 0.90.9655 hCV15954645 rs2954029 hCV29719123 rs6982636 0.51 0.9 0.9634hCV15954645 rs2954029 hCV309481 rs2954019 0.51 0.9 0.9655 hCV15954645rs2954029 hCV469160 rs2954031 0.51 0.9 0.9652 hCV15954645 rs2954029hCV85515 rs10808546 0.51 0.9 0.9627 hCV15954645 rs2954029 hDV70938014rs17321515 0.51 0.9 0.9634 hCV15963535 rs2228591 hCV1685900 rs119891730.51 0.9 1 hCV15963535 rs2228591 hCV1685923 rs11986247 0.51 0.9 1hCV15963535 rs2228591 hCV1685972 rs11993681 0.51 0.9 1 hCV15963535rs2228591 hCV1685995 rs4737303 0.51 0.9 1 hCV15963535 rs2228591hCV1685996 rs11986140 0.51 0.9 1 hCV15963535 rs2228591 hCV1747726rs1046013 0.51 0.9 1 hCV15963535 rs2228591 hCV26137599 rs4236981 0.510.9 1 hCV15963535 rs2228591 hCV26137622 rs2290878 0.51 0.9 1 hCV15963535rs2228591 hCV26137632 rs4236983 0.51 0.9 1 hCV15963535 rs2228591hCV27988605 rs4738086 0.51 0.9 1 hCV15963535 rs2228591 hCV28010537rs4738085 0.51 0.9 1 hCV15963535 rs2228591 hCV28966688 rs6985242 0.510.9 1 hCV15963535 rs2228591 hCV28966697 rs7824655 0.51 0.9 1 hCV15963535rs2228591 hCV29002921 rs6980582 0.51 0.9 1 hCV15963535 rs2228591hCV29769542 rs10435576 0.51 0.9 1 hCV15963535 rs2228591 hCV30095235rs10504468 0.51 0.9 1 hCV15963535 rs2228591 hCV30711319 rs11990849 0.510.9 1 hCV15963535 rs2228591 hCV30711334 rs12056650 0.51 0.9 1hCV15963535 rs2228591 hCV30820702 rs12056770 0.51 0.9 1 hCV15963535rs2228591 hCV30820703 rs4738072 0.51 0.9 1 hCV15963535 rs2228591hCV32300506 rs4738084 0.51 0.9 1 hCV15963535 rs2228591 hCV8340770rs3892265 0.51 0.9 1 hCV15963535 rs2228591 hDV70748336 rs16936768 0.510.9 1 hCV15963535 rs2228591 hDV70748364 rs16936806 0.51 0.9 1hCV15963535 rs2228591 hDV70748367 rs16936812 0.51 0.9 1 hCV15963535rs2228591 hDV70748369 rs16936814 0.51 0.9 1 hCV15963535 rs2228591hDV70748371 rs16936816 0.51 0.9 1 hCV15963535 rs2228591 hDV70748397rs16936858 0.51 0.9 1 hCV15963535 rs2228591 hDV70748406 rs16936875 0.510.9 1 hCV15963535 rs2228591 hDV70748417 rs16936890 0.51 0.9 1hCV15963535 rs2228591 hDV70748418 rs16936891 0.51 0.9 1 hCV15963535rs2228591 hDV70748437 rs16936913 0.51 0.9 1 hCV15963535 rs2228591hDV70748439 rs16936916 0.51 0.9 1 hCV15963535 rs2228591 hDV70748441rs16936918 0.51 0.9 1 hCV15963535 rs2228591 hDV70748443 rs16936921 0.510.9 1 hCV15963535 rs2228591 hDV70748446 rs16936925 0.51 0.9 1hCV15963535 rs2228591 hDV70748455 rs16936937 0.51 0.9 1 hCV15963535rs2228591 hDV70748457 rs16936940 0.51 0.9 1 hCV15963535 rs2228591hDV70748474 rs16936971 0.51 0.9 1 hCV15963535 rs2228591 hDV71598930rs16936746 0.51 0.9 1 hCV15963535 rs2228591 hDV71598935 rs16936923 0.510.9 1 hCV15963535 rs2228591 hDV77039578 rs4738081 0.51 0.9 1 hCV15963535rs2228591 hDV81067598 rs41391448 0.51 0.9 1 hCV16065831 rs2765507hCV1188662 rs4908519 0.51 0.77524667 1 hCV16065831 rs2765507 hCV15932989rs2781064 0.51 0.77524667 1 hCV16140621 rs2156552 hCV15846640 rs21873750.51 0.9 1 hCV16140621 rs2156552 hCV27889421 rs4939883 0.51 0.9 0.9392hCV16140621 rs2156552 hCV29202191 rs7240405 0.51 0.9 0.9694 hCV16140621rs2156552 hCV29202193 rs7239867 0.51 0.9 0.9694 hCV16140621 rs2156552hCV29202195 rs8086351 0.51 0.9 1 hCV16140621 rs2156552 hCV30011938rs7241918 0.51 0.9 0.9366 hCV16140621 rs2156552 hCV30606396 rs104389780.51 0.9 0.9392 hCV16140621 rs2156552 hDV71197604 rs1943981 0.51 0.9 1hCV16173091 rs2241883 hCV7933022 rs1545223 0.51 0.9 0.9789 hCV16179628rs2273697 hCV31656838 rs11190291 0.51 0.9 1 hCV16179628 rs2273697hCV31656920 rs11595888 0.51 0.9 1 hCV16182835 rs2274736 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0.8212 hCV26683368 rs2004580hDV70590478 rs9897338 0.51 0.600149065 0.8212 hCV26683368 rs2004580hDV70977122 rs17616652 0.51 0.600149065 0.6405 hCV26683368 rs2004580hDV75285090 rs2667804 0.51 0.600149065 0.9076 hCV2741051 rs2230806hCV15808302 rs2253182 0.51 0.9 1 hCV2741051 rs2230806 hCV15808303rs2253175 0.51 0.9 1 hCV2741051 rs2230806 hCV15808304 rs2253172 0.51 0.91 hCV2741051 rs2230806 hCV16235439 rs2472384 0.51 0.9 1 hCV2741051rs2230806 hCV16235449 rs2253174 0.51 0.9 1 hCV2741051 rs2230806hCV16235556 rs2253304 0.51 0.9 1 hCV2741051 rs2230806 hCV16235566rs2472439 0.51 0.9 0.9413 hCV2741051 rs2230806 hCV2960435 rs2472433 0.510.9 0.9705 hCV2741083 rs4149313 hCV2741071 rs7031748 0.51 0.9 0.9603hCV2741083 rs4149313 hCV2741079 rs4149310 0.51 0.9 1 hCV2741083rs4149313 hCV2741080 rs3780543 0.51 0.9 0.9603 hCV2741083 rs4149313hCV27979351 rs4149311 0.51 0.9 0.9603 hCV2741083 rs4149313 hCV9306688rs4743762 0.51 0.9 0.9603 hCV27422538 rs6940254 hCV11226249 rs64150850.51 0.459494331 0.5362 hCV27422538 rs6940254 hCV11285578 rs6926458 0.510.459494331 1 hCV27422538 rs6940254 hCV11846435 rs6929299 0.510.459494331 0.5349 hCV27422538 rs6940254 hCV1550866 rs6932014 0.510.459494331 0.5362 hCV27422538 rs6940254 hCV243055 rs10945682 0.510.459494331 0.5349 hCV27422538 rs6940254 hCV249895 rs7771129 0.510.459494331 0.5362 hCV27422538 rs6940254 hCV249898 rs9456552 0.510.459494331 0.55 hCV27422538 rs6940254 hCV25927459 rs3798221 0.510.459494331 0.6129 hCV27422538 rs6940254 hCV26272388 rs7770685 0.510.459494331 1 hCV27422538 rs6940254 hCV26272389 rs7760585 0.510.459494331 0.5349 hCV27422538 rs6940254 hCV27422546 rs7761377 0.510.459494331 0.5504 hCV27422538 rs6940254 hCV27422547 rs6455696 0.510.459494331 0.5336 hCV27422538 rs6940254 hCV27422554 rs6923917 0.510.459494331 0.5349 hCV27422538 rs6940254 hCV27422556 rs9355814 0.510.459494331 0.5659 hCV27422538 rs6940254 hCV27422557 rs9355813 0.510.459494331 0.5875 hCV27422538 rs6940254 hCV27422565 rs13202636 0.510.459494331 1 hCV27422538 rs6940254 hCV29709361 rs9365179 0.510.459494331 0.5152 hCV27422538 rs6940254 hCV29817515 rs9355817 0.510.459494331 0.51 hCV27422538 rs6940254 hCV29934611 rs9295130 0.510.459494331 0.5291 hCV27422538 rs6940254 hCV305046 rs6902102 0.510.459494331 0.5232 hCV27422538 rs6940254 hCV31882494 rs12175867 0.510.459494331 1 hCV27422538 rs6940254 hCV3201490 rs1321195 0.510.459494331 0.6 hCV27422538 rs6940254 hCV3201495 rs1367210 0.510.459494331 0.6129 hCV27422538 rs6940254 hCV3201497 rs1321196 0.510.459494331 0.5349 hCV27422538 rs6940254 hCV8701273 rs783148 0.510.459494331 0.6 hCV27422538 rs6940254 hCV8710154 rs1569933 0.510.459494331 0.5291 hCV27422538 rs6940254 hCV8710161 rs1740428 0.510.459494331 0.5349 hCV27422538 rs6940254 hDV77235995 rs7746273 0.510.459494331 0.5362 hCV27462774 rs3127583 hCV16149755 rs2183470 0.510.708469605 1 hCV27462774 rs3127583 hCV16149755 rs2183470 0.510.756245335 1 hCV27462774 rs3127583 hCV27397381 rs3120149 0.510.708469605 1 hCV27462774 rs3127583 hCV27397381 rs3120149 0.510.756245335 1 hCV27462774 rs3127583 hCV27455194 rs3103347 0.510.708469605 0.9667 hCV27462774 rs3127583 hCV27455194 rs3103347 0.510.756245335 0.9667 hCV27462774 rs3127583 hCV27459536 rs3119310 0.510.708469605 0.776 hCV27462774 rs3127583 hCV27459536 rs3119310 0.510.756245335 0.776 hCV27462774 rs3127583 hCV27460663 rs3120137 0.510.708469605 0.9011 hCV27462774 rs3127583 hCV27460663 rs3120137 0.510.756245335 0.9011 hCV27462774 rs3127583 hCV27461119 rs3125056 0.510.708469605 0.8336 hCV27462774 rs3127583 hCV27461119 rs3125056 0.510.756245335 0.8336 hCV27462774 rs3127583 hCV27462007 rs3127578 0.510.708469605 0.776 hCV27462774 rs3127583 hCV27462007 rs3127578 0.510.756245335 0.776 hCV27462774 rs3127583 hCV27462671 rs3120139 0.510.708469605 1 hCV27462774 rs3127583 hCV27462671 rs3120139 0.510.756245335 1 hCV27462774 rs3127583 hCV27464241 rs3125052 0.510.708469605 1 hCV27462774 rs3127583 hCV27464241 rs3125052 0.510.756245335 1 hCV27462774 rs3127583 hCV27464790 rs3127591 0.510.708469605 0.9135 hCV27462774 rs3127583 hCV27464790 rs3127591 0.510.756245335 0.9135 hCV27462774 rs3127583 hCV30977815 rs3127597 0.510.708469605 0.8905 hCV27462774 rs3127583 hCV30977815 rs3127597 0.510.756245335 0.8905 hCV27462774 rs3127583 hCV30977817 rs3106168 0.510.708469605 1 hCV27462774 rs3127583 hCV30977817 rs3106168 0.510.756245335 1 hCV27462774 rs3127583 hCV30977839 rs3120140 0.510.708469605 0.8656 hCV27462774 rs3127583 hCV30977839 rs3120140 0.510.756245335 0.8656 hCV27462774 rs3127583 hCV30977855 rs3103350 0.510.708469605 1 hCV27462774 rs3127583 hCV30977855 rs3103350 0.510.756245335 1 hCV27462774 rs3127583 hCV31605072 rs12206585 0.510.708469605 1 hCV27462774 rs3127583 hCV31605072 rs12206585 0.510.756245335 1 hCV27462774 rs3127583 hCV31605081 rs12203303 0.510.708469605 0.8994 hCV27462774 rs3127583 hCV31605081 rs12203303 0.510.756245335 0.8994 hCV27462774 rs3127583 hCV32312668 rs3103349 0.510.708469605 1 hCV27462774 rs3127583 hCV32312668 rs3103349 0.510.756245335 1 hCV27462774 rs3127583 hDV71669191 rs3127586 0.510.708469605 1 hCV27462774 rs3127583 hDV71669191 rs3127586 0.510.756245335 1 hCV27462774 rs3127583 hDV75428625 rs3106167 0.510.708469605 1 hCV27462774 rs3127583 hDV75428625 rs3106167 0.510.756245335 1 hCV27462774 rs3127583 hDV75428626 rs3106170 0.510.708469605 1 hCV27462774 rs3127583 hDV75428626 rs3106170 0.510.756245335 1 hCV27462774 rs3127583 hDV75428628 rs3106172 0.510.708469605 1 hCV27462774 rs3127583 hDV75428628 rs3106172 0.510.756245335 1 hCV27462774 rs3127583 hDV75431938 rs3120151 0.510.708469605 1 hCV27462774 rs3127583 hDV75431938 rs3120151 0.510.756245335 1 hCV27462774 rs3127583 hDV75433616 rs3125049 0.510.708469605 0.9278 hCV27462774 rs3127583 hDV75433616 rs3125049 0.510.756245335 0.9278 hCV27462774 rs3127583 hDV75433617 rs3125050 0.510.708469605 1 hCV27462774 rs3127583 hDV75433617 rs3125050 0.510.756245335 1 hCV27462774 rs3127583 hDV75433619 rs3125055 0.510.708469605 0.7337 hCV27480853 rs3766430 hCV2431627 rs646534 0.51 0.90.9437 hCV27480853 rs3766430 hCV27498227 rs3766431 0.51 0.9 0.9805hCV27480853 rs3766430 hCV27498228 rs3766436 0.51 0.9 0.9643 hCV27480853rs3766430 hCV27924561 rs4927080 0.51 0.9 0.9264 hCV27480853 rs3766430hCV29234422 rs3766437 0.51 0.9 0.9643 hCV2762168 rs3939286 hCV12096527rs1888909 0.51 0.9 0.9767 hCV2762168 rs3939286 hCV12096531 rs928413 0.510.9 0.9767 hCV2762168 rs3939286 hCV16108911 rs2095044 0.51 0.9 0.9616hCV2762168 rs3939286 hCV16225421 rs2381416 0.51 0.9 0.9252 hCV2762168rs3939286 hCV31940459 rs7848215 0.51 0.9 0.9252 hCV2762168 rs3939286hCV8785827 rs992969 0.51 0.9 1 hCV2769554 rs1805010 hCV2769561 rs30245480.51 0.9 1 hCV2769554 rs1805010 hCV2769568 rs3024530 0.51 0.9 0.926hCV2781953 rs6021931 hCV11182690 rs13045199 0.51 0.9 0.9391 hCV2781953rs6021931 hCV2487050 rs17806278 0.51 0.9 0.9391 hCV2781953 rs6021931hCV2487054 rs13043303 0.51 0.9 1 hCV2781953 rs6021931 hCV2487070rs6091546 0.51 0.9 1 hCV2781953 rs6021931 hCV2487071 rs1473705 0.51 0.91 hCV2781953 rs6021931 hCV2487073 rs17806379 0.51 0.9 0.9393 hCV2781953rs6021931 hCV2487087 rs13037630 0.51 0.9 1 hCV2781953 rs6021931hCV2516638 rs13037010 0.51 0.9 0.942 hCV2781953 rs6021931 hCV2781950rs6096949 0.51 0.9 1 hCV2781953 rs6021931 hCV2781958 rs6096956 0.51 0.90.9694 hCV2781953 rs6021931 hCV2781970 rs17806224 0.51 0.9 1 hCV2781953rs6021931 hCV31734434 rs13039375 0.51 0.9 1 hCV2781953 rs6021931hCV31734442 rs13039956 0.51 0.9 1 hCV2781953 rs6021931 hDV71605793rs17203653 0.51 0.9 1 hCV27884601 rs4908776 hCV1188731 rs4908514 0.510.900202572 1 hCV27884601 rs4908776 hCV1188735 rs10864366 0.510.900202572 1 hCV27884601 rs4908776 hCV27157507 rs6664000 0.510.900202572 1 hCV27884601 rs4908776 hCV27157524 rs6577531 0.510.900202572 0.9351 hCV27884601 rs4908776 hCV28023091 rs4908773 0.510.900202572 1 hCV27884601 rs4908776 hCV29368919 rs4908513 0.510.900202572 1 hCV27884601 rs4908776 hCV29873524 rs7533113 0.510.900202572 1 hCV27884601 rs4908776 hCV29945430 rs7517436 0.510.900202572 1 hCV27884601 rs4908776 hCV30035535 rs7518204 0.510.900202572 1 hCV27884601 rs4908776 hCV32055527 rs10864364 0.510.900202572 1 hCV27884601 rs4908776 hCV32055579 rs6577522 0.510.900202572 1 hCV27884601 rs4908776 hCV32055595 rs6577524 0.510.900202572 1 hCV27884601 rs4908776 hCV32055596 rs6577525 0.510.900202572 1 hCV27884601 rs4908776 hCV32055637 rs6577532 0.510.900202572 0.9312 hCV27884601 rs4908776 hCV8823713 rs1472228 0.510.900202572 1 hCV27958354 rs4908762 hCV29873526 rs6697997 0.510.969446018 1 hCV27958354 rs4908762 hCV3086998 rs7530863 0.510.969446018 1 hCV27958354 rs4908762 hCV3087000 rs1463055 0.510.969446018 1 hCV27958354 rs4908762 hCV3087003 rs6577500 0.510.969446018 1 hCV27958354 rs4908762 hCV3087015 rs11121198 0.510.969446018 1 hCV27958354 rs4908762 hCV32055548 rs11121197 0.510.969446018 1 hCV27958354 rs4908762 hCV32055677 rs10864355 0.510.969446018 1 hCV27958354 rs4908762 hCV529178 rs301811 0.51 0.9694460181 hCV27958354 rs4908762 hCV597227 rs301809 0.51 0.969446018 1hCV27958354 rs4908762 hCV597229 rs301785 0.51 0.969446018 1 hCV27958354rs4908762 hCV8824288 rs910582 0.51 0.969446018 1 hCV27958354 rs4908762hCV8881161 rs926951 0.51 0.969446018 1 hCV28008078 rs4745543 hCV11765753rs3793456 0.51 0.766415386 0.8388 hCV28008078 rs4745543 hCV1463112rs3763608 0.51 0.766415386 1 hCV28008078 rs4745543 hCV1463244 rs37934650.51 0.766415386 0.827 hCV28008078 rs4745543 hCV1463252 rs3793461 0.510.766415386 0.8689 hCV28008078 rs4745543 hCV15761059 rs2309393 0.510.766415386 0.827 hCV28008078 rs4745543 hCV26566199 rs3793467 0.510.766415386 0.8689 hCV28008078 rs4745543 hCV30586985 rs10126006 0.510.766415386 0.8573 hCV28008078 rs4745543 hCV31363797 rs11145043 0.510.766415386 0.792 hCV28008078 rs4745543 hCV31363840 rs7875693 0.510.766415386 0.7884 hCV28008078 rs4745543 hCV31363841 rs7849347 0.510.766415386 0.8065 hCV28008078 rs4745543 hCV31363984 rs7855905 0.510.766415386 0.792 hCV28023091 rs4908773 hCV11398434 rs1812457 0.510.495466362 0.7979 hCV28023091 rs4908773 hCV11398437 rs1817367 0.510.495466362 0.6548 hCV28023091 rs4908773 hCV11675962 rs10746481 0.510.495466362 0.8704 hCV28023091 rs4908773 hCV1188659 rs3820037 0.510.495466362 0.5447 hCV28023091 rs4908773 hCV1188660 rs6660137 0.510.495466362 0.5538 hCV28023091 rs4908773 hCV1188664 rs2765511 0.510.495466362 0.6126 hCV28023091 rs4908773 hCV1188665 rs2781060 0.510.495466362 0.6354 hCV28023091 rs4908773 hCV1188676 rs11121247 0.510.495466362 0.5538 hCV28023091 rs4908773 hCV1188731 rs4908514 0.510.495466362 1 hCV28023091 rs4908773 hCV1188735 rs10864366 0.510.495466362 1 hCV28023091 rs4908773 hCV12040675 rs2038904 0.510.495466362 0.6126 hCV28023091 rs4908773 hCV15882429 rs2289732 0.510.495466362 0.6247 hCV28023091 rs4908773 hCV15932991 rs2781067 0.510.495466362 0.6188 hCV28023091 rs4908773 hCV15932992 rs2781068 0.510.495466362 0.6121 hCV28023091 rs4908773 hCV27157507 rs6664000 0.510.495466362 1 hCV28023091 rs4908773 hCV27157524 rs6577531 0.510.495466362 0.9314 hCV28023091 rs4908773 hCV2741759 rs11121179 0.510.495466362 0.6713 hCV28023091 rs4908773 hCV27474399 rs3753275 0.510.495466362 0.5807 hCV28023091 rs4908773 hCV27884601 rs4908776 0.510.495466362 1 hCV28023091 rs4908773 hCV27958354 rs4908762 0.510.495466362 0.6717 hCV28023091 rs4908773 hCV29368919 rs4908513 0.510.495466362 1 hCV28023091 rs4908773 hCV2943451 rs902355 0.51 0.4954663620.7098 hCV28023091 rs4908773 hCV2943853 rs301793 0.51 0.495466362 0.6247hCV28023091 rs4908773 hCV2966436 rs11121174 0.51 0.495466362 0.6247hCV28023091 rs4908773 hCV2966437 rs11580417 0.51 0.495466362 0.6247hCV28023091 rs4908773 hCV2966441 rs6684863 0.51 0.495466362 0.6247hCV28023091 rs4908773 hCV2966444 rs11121171 0.51 0.495466362 0.6727hCV28023091 rs4908773 hCV29819064 rs6698079 0.51 0.495466362 0.7458hCV28023091 rs4908773 hCV2987250 rs301810 0.51 0.495466362 0.5105hCV28023091 rs4908773 hCV29873524 rs7533113 0.51 0.495466362 1hCV28023091 rs4908773 hCV29873526 rs6697997 0.51 0.495466362 0.6952hCV28023091 rs4908773 hCV29945430 rs7517436 0.51 0.495466362 1hCV28023091 rs4908773 hCV30035535 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0.51 0.495466362 0.6676hCV28023091 rs4908773 hCV32055470 rs6577506 0.51 0.495466362 0.7188hCV28023091 rs4908773 hCV32055474 rs10864359 0.51 0.495466362 0.6717hCV28023091 rs4908773 hCV32055477 rs10779705 0.51 0.495466362 0.7979hCV28023091 rs4908773 hCV32055527 rs10864364 0.51 0.495466362 1hCV28023091 rs4908773 hCV32055548 rs11121197 0.51 0.495466362 0.6952hCV28023091 rs4908773 hCV32055579 rs6577522 0.51 0.495466362 1hCV28023091 rs4908773 hCV32055595 rs6577524 0.51 0.495466362 1hCV28023091 rs4908773 hCV32055596 rs6577525 0.51 0.495466362 1hCV28023091 rs4908773 hCV32055625 rs6678590 0.51 0.495466362 0.8645hCV28023091 rs4908773 hCV32055637 rs6577532 0.51 0.495466362 0.8301hCV28023091 rs4908773 hCV32055662 rs6677249 0.51 0.495466362 0.645hCV28023091 rs4908773 hCV32055677 rs10864355 0.51 0.495466362 0.6952hCV28023091 rs4908773 hCV529178 rs301811 0.51 0.495466362 0.6949hCV28023091 rs4908773 hCV529182 rs301800 0.51 0.495466362 0.6998hCV28023091 rs4908773 hCV597227 rs301809 0.51 0.495466362 0.6952hCV28023091 rs4908773 hCV597229 rs301785 0.51 0.495466362 0.6952hCV28023091 rs4908773 hCV877241 rs301788 0.51 0.495466362 0.6713hCV28023091 rs4908773 hCV8823713 rs1472228 0.51 0.495466362 1hCV28023091 rs4908773 hCV8824244 rs1006950 0.51 0.495466362 0.574hCV28023091 rs4908773 hCV8824248 rs1543711 0.51 0.495466362 0.6126hCV28023091 rs4908773 hCV8824288 rs910582 0.51 0.495466362 0.6952hCV28023091 rs4908773 hCV8824394 rs1443929 0.51 0.495466362 0.6713hCV28023091 rs4908773 hCV8824424 rs1058790 0.51 0.495466362 0.6727hCV28023091 rs4908773 hCV8824425 rs1058791 0.51 0.495466362 0.6383hCV28023091 rs4908773 hCV8881145 rs1038008 0.51 0.495466362 0.7979hCV28023091 rs4908773 hCV8881146 rs1463054 0.51 0.495466362 0.8032hCV28023091 rs4908773 hCV8881157 rs1535158 0.51 0.495466362 0.7979hCV28023091 rs4908773 hCV8881161 rs926951 0.51 0.495466362 0.6717hCV282793 rs11751605 hCV30977815 rs3127597 0.51 0.782580889 0.801hCV28960526 rs6853079 hCV28960525 rs6532740 0.51 0.9 1 hCV28960526rs6853079 hCV29480044 rs10516433 0.51 0.9 1 hCV28960526 rs6853079hCV30454150 rs10516434 0.51 0.9 0.9309 hCV28960526 rs6853079 hCV30694936rs6840610 0.51 0.9 1 hCV28960526 rs6853079 hDV70961198 rs17498778 0.510.9 1 hCV28960526 rs6853079 hDV70961229 rs17499015 0.51 0.9 0.9398hCV28960526 rs6853079 hDV70969482 rs17564872 0.51 0.9 1 hCV28960526rs6853079 hDV71951446 rs7689289 0.51 0.9 1 hCV28974083 rs8032553hCV26066881 rs11629584 0.51 0.9 1 hCV28974083 rs8032553 hCV30732106rs4556765 0.51 0.9 0.9647 hCV28974083 rs8032553 hCV31590435 rs116345710.51 0.9 0.9634 hCV29011391 rs7557067 hCV11168524 rs6544366 0.51 0.9 1hCV29011391 rs7557067 hCV11168530 rs6728178 0.51 0.9 1 hCV29011391rs7557067 hCV260164 rs6754295 0.51 0.9 1 hCV29011391 rs7557067hCV27912761 rs4564803 0.51 0.9 1 hCV29011391 rs7557067 hCV30455594rs10184054 0.51 0.9 1 hCV29011391 rs7557067 hCV30847428 rs11902417 0.510.9 1 hCV29135108 rs6743779 hCV2772191 rs10170608 0.51 0.9 0.9005hCV2932115 rs5517 hCV1531092 rs3745522 0.51 0.9 0.9476 hCV2932115 rs5517hCV29188580 rs3212820 0.51 0.9 1 hCV2932115 rs5517 hCV2932116 rs55190.51 0.9 1 hCV29322781 rs6921516 hCV103951 rs6455688 0.51 0.4653366620.9792 hCV29322781 rs6921516 hCV103951 rs6455688 0.51 0.622712349 0.9792hCV29322781 rs6921516 hCV103952 rs6923877 0.51 0.465336662 0.9792hCV29322781 rs6921516 hCV103952 rs6923877 0.51 0.622712349 0.9792hCV29322781 rs6921516 hCV11226249 rs6415085 0.51 0.465336662 0.7601hCV29322781 rs6921516 hCV11226249 rs6415085 0.51 0.622712349 0.7601hCV29322781 rs6921516 hCV11284288 rs9457946 0.51 0.465336662 1hCV29322781 rs6921516 hCV11284288 rs9457946 0.51 0.622712349 1hCV29322781 rs6921516 hCV11846435 rs6929299 0.51 0.465336662 0.8326hCV29322781 rs6921516 hCV11846435 rs6929299 0.51 0.622712349 0.8326hCV29322781 rs6921516 hCV1550866 rs6932014 0.51 0.465336662 0.7601hCV29322781 rs6921516 hCV1550866 rs6932014 0.51 0.622712349 0.7601hCV29322781 rs6921516 hCV1550871 rs9355295 0.51 0.465336662 1hCV29322781 rs6921516 hCV1550871 rs9355295 0.51 0.622712349 1hCV29322781 rs6921516 hCV207123 rs7771801 0.51 0.465336662 1 hCV29322781rs6921516 hCV207123 rs7771801 0.51 0.622712349 1 hCV29322781 rs6921516hCV207127 rs7453899 0.51 0.465336662 0.9795 hCV29322781 rs6921516hCV207127 rs7453899 0.51 0.622712349 0.9795 hCV29322781 rs6921516hCV207128 rs6455689 0.51 0.465336662 0.9184 hCV29322781 rs6921516hCV207128 rs6455689 0.51 0.622712349 0.9184 hCV29322781 rs6921516hCV243055 rs10945682 0.51 0.465336662 0.8334 hCV29322781 rs6921516hCV243055 rs10945682 0.51 0.622712349 0.8334 hCV29322781 rs6921516hCV249895 rs7771129 0.51 0.465336662 0.7601 hCV29322781 rs6921516hCV249895 rs7771129 0.51 0.622712349 0.7601 hCV29322781 rs6921516hCV249897 rs6913833 0.51 0.465336662 0.6796 hCV29322781 rs6921516hCV249897 rs6913833 0.51 0.622712349 0.6796 hCV29322781 rs6921516hCV249898 rs9456552 0.51 0.465336662 0.7704 hCV29322781 rs6921516hCV249898 rs9456552 0.51 0.622712349 0.7704 hCV29322781 rs6921516hCV25929408 rs7765781 0.51 0.465336662 1 hCV29322781 rs6921516hCV25929408 rs7765781 0.51 0.622712349 1 hCV29322781 rs6921516hCV25929478 rs7765803 0.51 0.465336662 0.9795 hCV29322781 rs6921516hCV25929478 rs7765803 0.51 0.622712349 0.9795 hCV29322781 rs6921516hCV26272389 rs7760585 0.51 0.465336662 0.8334 hCV29322781 rs6921516hCV26272389 rs7760585 0.51 0.622712349 0.8334 hCV29322781 rs6921516hCV27422546 rs7761377 0.51 0.465336662 0.722 hCV29322781 rs6921516hCV27422546 rs7761377 0.51 0.622712349 0.722 hCV29322781 rs6921516hCV27422547 rs6455696 0.51 0.465336662 0.7271 hCV29322781 rs6921516hCV27422547 rs6455696 0.51 0.622712349 0.7271 hCV29322781 rs6921516hCV27422554 rs6923917 0.51 0.465336662 0.8334 hCV29322781 rs6921516hCV27422554 rs6923917 0.51 0.622712349 0.8334 hCV29322781 rs6921516hCV27422556 rs9355814 0.51 0.465336662 0.7413 hCV29322781 rs6921516hCV27422556 rs9355814 0.51 0.622712349 0.7413 hCV29322781 rs6921516hCV27422557 rs9355813 0.51 0.465336662 0.767 hCV29322781 rs6921516hCV27422557 rs9355813 0.51 0.622712349 0.767 hCV29322781 rs6921516hCV27422575 rs6415084 0.51 0.465336662 0.4788 hCV29322781 rs6921516hCV29546641 rs9365171 0.51 0.465336662 0.8819 hCV29322781 rs6921516hCV29546641 rs9365171 0.51 0.622712349 0.8819 hCV29322781 rs6921516hCV29709361 rs9365179 0.51 0.465336662 0.8171 hCV29322781 rs6921516hCV29709361 rs9365179 0.51 0.622712349 0.8171 hCV29322781 rs6921516hCV29817515 rs9355817 0.51 0.465336662 0.6883 hCV29322781 rs6921516hCV29817515 rs9355817 0.51 0.622712349 0.6883 hCV29322781 rs6921516hCV29934611 rs9295130 0.51 0.465336662 0.8152 hCV29322781 rs6921516hCV29934611 rs9295130 0.51 0.622712349 0.8152 hCV29322781 rs6921516hCV29998162 rs9457943 0.51 0.465336662 1 hCV29322781 rs6921516hCV29998162 rs9457943 0.51 0.622712349 1 hCV29322781 rs6921516 hCV305046rs6902102 0.51 0.465336662 0.7529 hCV29322781 rs6921516 hCV305046rs6902102 0.51 0.622712349 0.7529 hCV29322781 rs6921516 hCV30574599rs7770628 0.51 0.465336662 0.4698 hCV29322781 rs6921516 hCV3201494rs1367209 0.51 0.465336662 0.7291 hCV29322781 rs6921516 hCV3201494rs1367209 0.51 0.622712349 0.7291 hCV29322781 rs6921516 hCV3201497rs1321196 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV3201497rs1321196 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV8710154rs1569933 0.51 0.465336662 0.8274 hCV29322781 rs6921516 hCV8710154rs1569933 0.51 0.622712349 0.8274 hCV29322781 rs6921516 hCV8710161rs1740428 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV8710161rs1740428 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV8710162rs1367211 0.51 0.465336662 0.7291 hCV29322781 rs6921516 hCV8710162rs1367211 0.51 0.622712349 0.7291 hCV29322781 rs6921516 hDV77235995rs7746273 0.51 0.465336662 0.6915 hCV29322781 rs6921516 hDV77235995rs7746273 0.51 0.622712349 0.6915 hCV29368919 rs4908513 hCV11398434rs1812457 0.51 0.496733059 0.8094 hCV29368919 rs4908513 hCV11398437rs1817367 0.51 0.496733059 0.7755 hCV29368919 rs4908513 hCV11675962rs10746481 0.51 0.496733059 0.8774 hCV29368919 rs4908513 hCV1188659rs3820037 0.51 0.496733059 0.5968 hCV29368919 rs4908513 hCV1188660rs6660137 0.51 0.496733059 0.6126 hCV29368919 rs4908513 hCV1188664rs2765511 0.51 0.496733059 0.6312 hCV29368919 rs4908513 hCV1188665rs2781060 0.51 0.496733059 0.6541 hCV29368919 rs4908513 hCV1188676rs11121247 0.51 0.496733059 0.6126 hCV29368919 rs4908513 hCV1188731rs4908514 0.51 0.496733059 1 hCV29368919 rs4908513 hCV1188735 rs108643660.51 0.496733059 1 hCV29368919 rs4908513 hCV12040675 rs2038904 0.510.496733059 0.6312 hCV29368919 rs4908513 hCV15882429 rs2289732 0.510.496733059 0.6452 hCV29368919 rs4908513 hCV15932991 rs2781067 0.510.496733059 0.6396 hCV29368919 rs4908513 hCV15932992 rs2781068 0.510.496733059 0.6308 hCV29368919 rs4908513 hCV27157507 rs6664000 0.510.496733059 1 hCV29368919 rs4908513 hCV27157524 rs6577531 0.510.496733059 0.9353 hCV29368919 rs4908513 hCV27157546 rs11811795 0.510.496733059 0.5453 hCV29368919 rs4908513 hCV27157560 rs11121252 0.510.496733059 0.5135 hCV29368919 rs4908513 hCV2741759 rs11121179 0.510.496733059 0.6247 hCV29368919 rs4908513 hCV27884601 rs4908776 0.510.496733059 1 hCV29368919 rs4908513 hCV27958354 rs4908762 0.510.496733059 0.6952 hCV29368919 rs4908513 hCV28023091 rs4908773 0.510.496733059 1 hCV29368919 rs4908513 hCV2943451 rs902355 0.51 0.4967330590.7273 hCV29368919 rs4908513 hCV2943853 rs301793 0.51 0.496733059 0.6452hCV29368919 rs4908513 hCV2966436 rs11121174 0.51 0.496733059 0.6452hCV29368919 rs4908513 hCV2966437 rs11580417 0.51 0.496733059 0.6452hCV29368919 rs4908513 hCV2966441 rs6684863 0.51 0.496733059 0.6452hCV29368919 rs4908513 hCV2966444 rs11121171 0.51 0.496733059 0.6911hCV29368919 rs4908513 hCV29819064 rs6698079 0.51 0.496733059 0.7479hCV29368919 rs4908513 hCV2987250 rs301810 0.51 0.496733059 0.5341hCV29368919 rs4908513 hCV29873524 rs7533113 0.51 0.496733059 1hCV29368919 rs4908513 hCV29873526 rs6697997 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV29945430 rs7517436 0.51 0.496733059 1hCV29368919 rs4908513 hCV30035535 rs7518204 0.51 0.496733059 1hCV29368919 rs4908513 hCV30125699 rs4581300 0.51 0.496733059 0.6952hCV29368919 rs4908513 hCV30143725 rs6690050 0.51 0.496733059 0.7577hCV29368919 rs4908513 hCV30467730 rs6702457 0.51 0.496733059 0.8774hCV29368919 rs4908513 hCV3086930 rs6658881 0.51 0.496733059 0.8704hCV29368919 rs4908513 hCV3086932 rs7533442 0.51 0.496733059 0.8704hCV29368919 rs4908513 hCV3086950 rs4908771 0.51 0.496733059 0.8774hCV29368919 rs4908513 hCV3086961 rs6703577 0.51 0.496733059 0.7979hCV29368919 rs4908513 hCV3086971 rs6679948 0.51 0.496733059 0.8094hCV29368919 rs4908513 hCV3086972 rs6688329 0.51 0.496733059 0.8654hCV29368919 rs4908513 hCV3086998 rs7530863 0.51 0.496733059 0.6952hCV29368919 rs4908513 hCV3087000 rs1463055 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV3087003 rs6577500 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV3087015 rs11121198 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV3087016 rs2297867 0.51 0.496733059 0.6952hCV29368919 rs4908513 hCV32055284 rs12079653 0.51 0.496733059 0.6858hCV29368919 rs4908513 hCV32055470 rs6577506 0.51 0.496733059 0.7979hCV29368919 rs4908513 hCV32055474 rs10864359 0.51 0.496733059 0.7979hCV29368919 rs4908513 hCV32055477 rs10779705 0.51 0.496733059 0.8094hCV29368919 rs4908513 hCV32055527 rs10864364 0.51 0.496733059 1hCV29368919 rs4908513 hCV32055548 rs11121197 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV32055579 rs6577522 0.51 0.496733059 1hCV29368919 rs4908513 hCV32055595 rs6577524 0.51 0.496733059 1hCV29368919 rs4908513 hCV32055596 rs6577525 0.51 0.496733059 1hCV29368919 rs4908513 hCV32055625 rs6678590 0.51 0.496733059 0.879hCV29368919 rs4908513 hCV32055637 rs6577532 0.51 0.496733059 0.9314hCV29368919 rs4908513 hCV32055662 rs6677249 0.51 0.496733059 0.7437hCV29368919 rs4908513 hCV32055677 rs10864355 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV529178 rs301811 0.51 0.496733059 0.7109hCV29368919 rs4908513 hCV529182 rs301800 0.51 0.496733059 0.6732hCV29368919 rs4908513 hCV597227 rs301809 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV597229 rs301785 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV877241 rs301788 0.51 0.496733059 0.6247hCV29368919 rs4908513 hCV8823713 rs1472228 0.51 0.496733059 1hCV29368919 rs4908513 hCV8824241 rs1325920 0.51 0.496733059 0.5423hCV29368919 rs4908513 hCV8824244 rs1006950 0.51 0.496733059 0.6126hCV29368919 rs4908513 hCV8824248 rs1543711 0.51 0.496733059 0.6312hCV29368919 rs4908513 hCV8824288 rs910582 0.51 0.496733059 0.7112hCV29368919 rs4908513 hCV8824394 rs1443929 0.51 0.496733059 0.6247hCV29368919 rs4908513 hCV8824424 rs1058790 0.51 0.496733059 0.6911hCV29368919 rs4908513 hCV8824425 rs1058791 0.51 0.496733059 0.6721hCV29368919 rs4908513 hCV8881145 rs1038008 0.51 0.496733059 0.8094hCV29368919 rs4908513 hCV8881146 rs1463054 0.51 0.496733059 0.8042hCV29368919 rs4908513 hCV8881157 rs1535158 0.51 0.496733059 0.8094hCV29368919 rs4908513 hCV8881161 rs926951 0.51 0.496733059 0.6952hCV29480044 rs10516433 hCV28960525 rs6532740 0.51 0.9 1 hCV29480044rs10516433 hCV28960526 rs6853079 0.51 0.9 1 hCV29480044 rs10516433hCV30454150 rs10516434 0.51 0.9 0.9309 hCV29480044 rs10516433hCV30694936 rs6840610 0.51 0.9 1 hCV29480044 rs10516433 hDV70961198rs17498778 0.51 0.9 1 hCV29480044 rs10516433 hDV70961229 rs17499015 0.510.9 0.9398 hCV29480044 rs10516433 hDV70969482 rs17564872 0.51 0.9 1hCV29480044 rs10516433 hDV71951446 rs7689289 0.51 0.9 1 hCV2960489rs3785889 hCV10293 rs3851786 0.51 0.784117293 0.8104 hCV2960489rs3785889 hCV11623025 rs9898981 0.51 0.784117293 0.8121 hCV2960489rs3785889 hCV11623029 rs2316330 0.51 0.784117293 0.8195 hCV2960489rs3785889 hCV2275283 rs740617 0.51 0.784117293 0.7937 hCV2960489rs3785889 hCV2592671 rs197926 0.51 0.784117293 0.8209 hCV2960489rs3785889 hCV2592673 rs4968286 0.51 0.784117293 0.8591 hCV2960489rs3785889 hCV2592677 rs736604 0.51 0.784117293 0.8209 hCV2960489rs3785889 hCV2592681 rs17608961 0.51 0.784117293 0.8586 hCV2960489rs3785889 hCV26660327 rs11869840 0.51 0.784117293 0.8578 hCV2960489rs3785889 hCV29195266 rs3809854 0.51 0.784117293 0.8209 hCV2960489rs3785889 hCV2959464 rs3760377 0.51 0.784117293 0.8591 hCV2960489rs3785889 hCV2959466 rs6504622 0.51 0.784117293 0.8591 hCV2960489rs3785889 hCV30299603 rs9889762 0.51 0.784117293 0.8398 hCV2960489rs3785889 hCV31466218 rs11079745 0.51 0.784117293 0.8586 hCV2960489rs3785889 hCV31466219 rs11652318 0.51 0.784117293 0.8195 hCV2960489rs3785889 hCV7448063 rs736603 0.51 0.784117293 0.816 hCV2960489rs3785889 hCV7451199 rs3851785 0.51 0.784117293 0.8195 hCV2960489rs3785889 hCV7451217 rs1052586 0.51 0.784117293 0.8398 hCV29684678rs10486788 hCV11811746 rs12669397 0.51 0.9 0.9583 hCV29684678 rs10486788hCV2641110 rs6948282 0.51 0.9 0.9783 hCV29684678 rs10486788 hCV2641111rs13239842 0.51 0.9 0.9783 hCV29684678 rs10486788 hCV2641141 rs132362370.51 0.9 0.9583 hCV29684678 rs10486788 hCV2641147 rs13234986 0.51 0.9 1hCV29684678 rs10486788 hCV2641150 rs17169192 0.51 0.9 1 hCV29684678rs10486788 hCV26518087 rs12699759 0.51 0.9 0.9783 hCV29684678 rs10486788hCV31310415 rs12674430 0.51 0.9 1 hCV29684678 rs10486788 hCV31310435rs10950592 0.51 0.9 0.9184 hCV29684678 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rs6698079 hCV32055477 rs10779705 0.510.900593335 1 hCV29819064 rs6698079 hCV8881145 rs1038008 0.510.900593335 1 hCV29819064 rs6698079 hCV8881146 rs1463054 0.510.900593335 1 hCV29819064 rs6698079 hCV8881157 rs1535158 0.510.900593335 1 hCV2983035 rs9527026 hCV25611075 rs7997728 0.51 0.9 1hCV2983035 rs9527026 hCV29426416 rs8000084 0.51 0.9 1 hCV2983035rs9527026 hCV29426417 rs8001148 0.51 0.9 1 hCV2983035 rs9527026hCV29426429 rs7986435 0.51 0.9 1 hCV2983035 rs9527026 hCV29676871rs9527032 0.51 0.9 0.9428 hCV2983035 rs9527026 hCV29803144 rs79827260.51 0.9 1 hCV2983035 rs9527026 hCV2983036 rs9527025 0.51 0.9 1hCV2983035 rs9527026 hCV2983037 rs9536314 0.51 0.9 1 hCV2983035rs9527026 hCV2983038 rs9536313 0.51 0.9 1 hCV2983035 rs9527026hCV2983040 rs9527024 0.51 0.9 1 hCV2983035 rs9527026 hCV29929821rs9536239 0.51 0.9 1 hCV2983035 rs9527026 hCV30109848 rs9526990 0.51 0.91 hCV2983035 rs9527026 hCV30181994 rs9527022 0.51 0.9 1 hCV2983035rs9527026 hCV30217619 rs9527023 0.51 0.9 1 hCV2983035 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rs12136689hCV1417732 rs12128827 0.51 0.694720473 0.8134 hCV3087008 rs12136689hCV2943852 rs301795 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2958030 rs3765971 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2958031 rs2252865 0.51 0.694720473 0.7735 hCV3087008 rs12136689hCV2966430 rs2708633 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2966432 rs6678140 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2966435 rs894875 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2987217 rs301791 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2987218 rs301790 0.51 0.694720473 0.7225 hCV3087008 rs12136689hCV2987219 rs301789 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2987237 rs172531 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV2987238 rs301801 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV3086955 rs4908769 0.51 0.694720473 0.9612 hCV3087008 rs12136689hCV32055281 rs10779702 0.51 0.694720473 0.7735 hCV3087008 rs12136689hCV32055303 rs2784736 0.51 0.694720473 0.7018 hCV3087008 rs12136689hCV32055534 rs12125525 0.51 0.694720473 0.8589 hCV3087008 rs12136689hCV32055581 rs12123076 0.51 0.694720473 0.7789 hCV3087008 rs12136689hCV32055778 rs6577497 0.51 0.694720473 0.8349 hCV3087008 rs12136689hCV8823613 rs953043 0.51 0.694720473 0.8852 hCV3087008 rs12136689hCV8824315 rs302719 0.51 0.694720473 0.7018 hCV3087015 rs11121198hCV11398434 rs1812457 0.51 0.534576608 0.8824 hCV3087015 rs11121198hCV11398437 rs1817367 0.51 0.534576608 0.8638 hCV3087015 rs11121198hCV11675962 rs10746481 0.51 0.534576608 0.8248 hCV3087015 rs11121198hCV1188731 rs4908514 0.51 0.534576608 0.7112 hCV3087015 rs11121198hCV1188735 rs10864366 0.51 0.534576608 0.6952 hCV3087015 rs11121198hCV15882429 rs2289732 0.51 0.534576608 0.7153 hCV3087015 rs11121198hCV25996298 rs7535752 0.51 0.534576608 0.5809 hCV3087015 rs11121198hCV27157507 rs6664000 0.51 0.534576608 0.6952 hCV3087015 rs11121198hCV27157524 rs6577531 0.51 0.534576608 0.6596 hCV3087015 rs11121198hCV2741759 rs11121179 0.51 0.534576608 0.6996 hCV3087015 rs11121198hCV27474399 rs3753275 0.51 0.534576608 0.5827 hCV3087015 rs11121198hCV27884601 rs4908776 0.51 0.534576608 0.7103 hCV3087015 rs11121198hCV27958354 rs4908762 0.51 0.534576608 1 hCV3087015 rs11121198hCV28023091 rs4908773 0.51 0.534576608 0.6952 hCV3087015 rs11121198hCV29368919 rs4908513 0.51 0.534576608 0.7112 hCV3087015 rs11121198hCV2943451 rs902355 0.51 0.534576608 0.7442 hCV3087015 rs11121198hCV2943853 rs301793 0.51 0.534576608 0.7153 hCV3087015 rs11121198hCV2966436 rs11121174 0.51 0.534576608 0.7153 hCV3087015 rs11121198hCV2966437 rs11580417 0.51 0.534576608 0.7153 hCV3087015 rs11121198hCV2966441 rs6684863 0.51 0.534576608 0.7153 hCV3087015 rs11121198hCV2966444 rs11121171 0.51 0.534576608 0.7672 hCV3087015 rs11121198hCV29819064 rs6698079 0.51 0.534576608 0.8488 hCV3087015 rs11121198hCV2987250 rs301810 0.51 0.534576608 0.8909 hCV3087015 rs11121198hCV29873524 rs7533113 0.51 0.534576608 0.7112 hCV3087015 rs11121198hCV29873526 rs6697997 0.51 0.534576608 1 hCV3087015 rs11121198hCV29945430 rs7517436 0.51 0.534576608 0.6952 hCV3087015 rs11121198hCV30035535 rs7518204 0.51 0.534576608 0.7101 hCV3087015 rs11121198hCV30125699 rs4581300 0.51 0.534576608 1 hCV3087015 rs11121198hCV30143725 rs6690050 0.51 0.534576608 0.8248 hCV3087015 rs11121198hCV30467730 rs6702457 0.51 0.534576608 0.8248 hCV3087015 rs11121198hCV3086930 rs6658881 0.51 0.534576608 0.815 hCV3087015 rs11121198hCV3086932 rs7533442 0.51 0.534576608 0.815 hCV3087015 rs11121198hCV3086950 rs4908771 0.51 0.534576608 0.8248 hCV3087015 rs11121198hCV3086961 rs6703577 0.51 0.534576608 0.8759 hCV3087015 rs11121198hCV3086971 rs6679948 0.51 0.534576608 0.8824 hCV3087015 rs11121198hCV3086972 rs6688329 0.51 0.534576608 0.8759 hCV3087015 rs11121198hCV3086998 rs7530863 0.51 0.534576608 1 hCV3087015 rs11121198 hCV3087000rs1463055 0.51 0.534576608 1 hCV3087015 rs11121198 hCV3087003 rs65775000.51 0.534576608 1 hCV3087015 rs11121198 hCV3087016 rs2297867 0.510.534576608 1 hCV3087015 rs11121198 hCV32055284 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0.534576608 1 hCV3087015 rs11121198hCV877241 rs301788 0.51 0.534576608 0.6996 hCV3087015 rs11121198hCV8823713 rs1472228 0.51 0.534576608 0.6952 hCV3087015 rs11121198hCV8824288 rs910582 0.51 0.534576608 1 hCV3087015 rs11121198 hCV8824394rs1443929 0.51 0.534576608 0.6996 hCV3087015 rs11121198 hCV8824424rs1058790 0.51 0.534576608 0.7672 hCV3087015 rs11121198 hCV8824425rs1058791 0.51 0.534576608 0.754 hCV3087015 rs11121198 hCV8881145rs1038008 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV8881146rs1463054 0.51 0.534576608 0.8271 hCV3087015 rs11121198 hCV8881157rs1535158 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV8881161rs926951 0.51 0.534576608 1 hCV3087016 rs2297867 hCV27958354 rs49087620.51 0.936425384 0.9694 hCV3087016 rs2297867 hCV29873526 rs6697997 0.510.936425384 1 hCV3087016 rs2297867 hCV3086998 rs7530863 0.51 0.9364253840.9694 hCV3087016 rs2297867 hCV3087000 rs1463055 0.51 0.936425384 1hCV3087016 rs2297867 hCV3087003 rs6577500 0.51 0.936425384 1 hCV3087016rs2297867 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hCV11846435rs6929299 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV1550871rs9355295 0.51 0.325832601 0.3554 hCV3201490 rs1321195 hCV15975022rs2314852 0.51 0.325832601 0.3961 hCV3201490 rs1321195 hCV207123rs7771801 0.51 0.325832601 0.3429 hCV3201490 rs1321195 hCV207127rs7453899 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV207128rs6455689 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV243055rs10945682 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV249898rs9456552 0.51 0.325832601 0.3355 hCV3201490 rs1321195 hCV25927459rs3798221 0.51 0.325832601 0.6526 hCV3201490 rs1321195 hCV25929408rs7765781 0.51 0.325832601 0.3554 hCV3201490 rs1321195 hCV25929478rs7765803 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV26272388rs7770685 0.51 0.325832601 0.6129 hCV3201490 rs1321195 hCV26272389rs7760585 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV27422538rs6940254 0.51 0.325832601 0.6 hCV3201490 rs1321195 hCV27422546rs7761377 0.51 0.325832601 0.3287 hCV3201490 rs1321195 hCV27422554rs6923917 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV27422556rs9355814 0.51 0.325832601 0.3325 hCV3201490 rs1321195 hCV27422557rs9355813 0.51 0.325832601 0.3283 hCV3201490 rs1321195 hCV27422565rs13202636 0.51 0.325832601 0.6129 hCV3201490 rs1321195 hCV29322781rs6921516 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV29546641rs9365171 0.51 0.325832601 0.3342 hCV3201490 rs1321195 hCV29998162rs9457943 0.51 0.325832601 0.3554 hCV3201490 rs1321195 hCV31882494rs12175867 0.51 0.325832601 0.6 hCV3201490 rs1321195 hCV3201494rs1367209 0.51 0.325832601 0.4687 hCV3201490 rs1321195 hCV3201495rs1367210 0.51 0.325832601 1 hCV3201490 rs1321195 hCV3201497 rs13211960.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV8701273 rs783148 0.510.325832601 1 hCV3201490 rs1321195 hCV8710161 rs1740428 0.51 0.3258326010.3278 hCV3201490 rs1321195 hCV8710162 rs1367211 0.51 0.325832601 0.4687hCV32055474 rs10864359 hCV11398434 rs1812457 0.51 0.5160794 1hCV32055474 rs10864359 hCV11398437 rs1817367 0.51 0.5160794 0.8987hCV32055474 rs10864359 hCV11675962 rs10746481 0.51 0.5160794 0.9345hCV32055474 rs10864359 hCV1188731 rs4908514 0.51 0.5160794 0.7979hCV32055474 rs10864359 hCV1188735 rs10864366 0.51 0.5160794 0.6717hCV32055474 rs10864359 hCV15882429 rs2289732 0.51 0.5160794 0.5747hCV32055474 rs10864359 hCV15932991 rs2781067 0.51 0.5160794 0.5621hCV32055474 rs10864359 hCV27157507 rs6664000 0.51 0.5160794 0.6717hCV32055474 rs10864359 hCV27157524 rs6577531 0.51 0.5160794 0.7394hCV32055474 rs10864359 hCV2741759 rs11121179 0.51 0.5160794 0.5606hCV32055474 rs10864359 hCV27884601 rs4908776 0.51 0.5160794 0.7973hCV32055474 rs10864359 hCV27958354 rs4908762 0.51 0.5160794 0.8778hCV32055474 rs10864359 hCV28023091 rs4908773 0.51 0.5160794 0.6717hCV32055474 rs10864359 hCV29368919 rs4908513 0.51 0.5160794 0.7979hCV32055474 rs10864359 hCV2943451 rs902355 0.51 0.5160794 0.6535hCV32055474 rs10864359 hCV2943853 rs301793 0.51 0.5160794 0.5747hCV32055474 rs10864359 hCV2966436 rs11121174 0.51 0.5160794 0.5747hCV32055474 rs10864359 hCV2966437 rs11580417 0.51 0.5160794 0.5747hCV32055474 rs10864359 hCV2966441 rs6684863 0.51 0.5160794 0.5747hCV32055474 rs10864359 hCV2966444 rs11121171 0.51 0.5160794 0.6208hCV32055474 rs10864359 hCV29819064 rs6698079 0.51 0.5160794 1hCV32055474 rs10864359 hCV2987250 rs301810 0.51 0.5160794 0.665hCV32055474 rs10864359 hCV29873524 rs7533113 0.51 0.5160794 0.7979hCV32055474 rs10864359 hCV29873526 rs6697997 0.51 0.5160794 0.8759hCV32055474 rs10864359 hCV29945430 rs7517436 0.51 0.5160794 0.6717hCV32055474 rs10864359 hCV30035535 rs7518204 0.51 0.5160794 0.7971hCV32055474 rs10864359 hCV30125699 rs4581300 0.51 0.5160794 0.8169hCV32055474 rs10864359 hCV30143725 rs6690050 0.51 0.5160794 0.9345hCV32055474 rs10864359 hCV30467730 rs6702457 0.51 0.5160794 0.9345hCV32055474 rs10864359 hCV3086930 rs6658881 0.51 0.5160794 0.85hCV32055474 rs10864359 hCV3086932 rs7533442 0.51 0.5160794 0.85hCV32055474 rs10864359 hCV3086950 rs4908771 0.51 0.5160794 0.9345hCV32055474 rs10864359 hCV3086961 rs6703577 0.51 0.5160794 0.9379hCV32055474 rs10864359 hCV3086971 rs6679948 0.51 0.5160794 1 hCV32055474rs10864359 hCV3086972 rs6688329 0.51 0.5160794 1 hCV32055474 rs10864359hCV3086998 rs7530863 0.51 0.5160794 0.8778 hCV32055474 rs10864359hCV3087000 rs1463055 0.51 0.5160794 0.8759 hCV32055474 rs10864359hCV3087003 rs6577500 0.51 0.5160794 0.8759 hCV32055474 rs10864359hCV3087015 rs11121198 0.51 0.5160794 0.8759 hCV32055474 rs10864359hCV3087016 rs2297867 0.51 0.5160794 0.85 hCV32055474 rs10864359hCV32055284 rs12079653 0.51 0.5160794 0.6676 hCV32055474 rs10864359hCV32055470 rs6577506 0.51 0.5160794 0.9379 hCV32055474 rs10864359hCV32055477 rs10779705 0.51 0.5160794 1 hCV32055474 rs10864359hCV32055527 rs10864364 0.51 0.5160794 0.6717 hCV32055474 rs10864359hCV32055548 rs11121197 0.51 0.5160794 0.8759 hCV32055474 rs10864359hCV32055579 rs6577522 0.51 0.5160794 0.7977 hCV32055474 rs10864359hCV32055595 rs6577524 0.51 0.5160794 0.7979 hCV32055474 rs10864359hCV32055596 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hCV32055474 rs10864359 hCV8881157 rs15351580.51 0.5160794 1 hCV32055474 rs10864359 hCV8881161 rs926951 0.510.5160794 0.8778 hCV32055477 rs10779705 hCV11398434 rs1812457 0.510.519194102 1 hCV32055477 rs10779705 hCV11398437 rs1817367 0.510.519194102 1 hCV32055477 rs10779705 hCV11675962 rs10746481 0.510.519194102 0.9381 hCV32055477 rs10779705 hCV1188731 rs4908514 0.510.519194102 0.8094 hCV32055477 rs10779705 hCV1188735 rs10864366 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV15882429 rs2289732 0.510.519194102 0.5975 hCV32055477 rs10779705 hCV15932991 rs2781067 0.510.519194102 0.5861 hCV32055477 rs10779705 hCV27157507 rs6664000 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV27157524 rs6577531 0.510.519194102 0.7539 hCV32055477 rs10779705 hCV2741759 rs11121179 0.510.519194102 0.5747 hCV32055477 rs10779705 hCV27884601 rs4908776 0.510.519194102 0.8089 hCV32055477 rs10779705 hCV27958354 rs4908762 0.510.519194102 0.8759 hCV32055477 rs10779705 hCV28023091 rs4908773 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV29368919 rs4908513 0.510.519194102 0.8094 hCV32055477 rs10779705 hCV2943451 rs902355 0.510.519194102 0.6736 hCV32055477 rs10779705 hCV2943853 rs301793 0.510.519194102 0.5975 hCV32055477 rs10779705 hCV2966436 rs11121174 0.510.519194102 0.5975 hCV32055477 rs10779705 hCV2966437 rs11580417 0.510.519194102 0.5975 hCV32055477 rs10779705 hCV2966441 rs6684863 0.510.519194102 0.5975 hCV32055477 rs10779705 hCV2966444 rs11121171 0.510.519194102 0.6417 hCV32055477 rs10779705 hCV29819064 rs6698079 0.510.519194102 1 hCV32055477 rs10779705 hCV2987250 rs301810 0.510.519194102 0.6812 hCV32055477 rs10779705 hCV29873524 rs7533113 0.510.519194102 0.8094 hCV32055477 rs10779705 hCV29873526 rs6697997 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV29945430 rs7517436 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV30035535 rs7518204 0.510.519194102 0.8087 hCV32055477 rs10779705 hCV30125699 rs4581300 0.510.519194102 0.8759 hCV32055477 rs10779705 hCV30143725 rs6690050 0.510.519194102 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hCV32055477 rs10779705 hCV32055527 rs10864364 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV32055548 rs11121197 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV32055579 rs6577522 0.510.519194102 0.8092 hCV32055477 rs10779705 hCV32055595 rs6577524 0.510.519194102 0.8094 hCV32055477 rs10779705 hCV32055596 rs6577525 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV32055625 rs6678590 0.510.519194102 0.7684 hCV32055477 rs10779705 hCV32055637 rs6577532 0.510.519194102 0.7394 hCV32055477 rs10779705 hCV32055662 rs6677249 0.510.519194102 0.5758 hCV32055477 rs10779705 hCV32055677 rs10864355 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV529178 rs301811 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV529182 rs301800 0.510.519194102 0.6217 hCV32055477 rs10779705 hCV597227 rs301809 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV597229 rs301785 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV877241 rs301788 0.510.519194102 0.5747 hCV32055477 rs10779705 hCV8823713 rs1472228 0.510.519194102 0.7979 hCV32055477 rs10779705 hCV8824288 rs910582 0.510.519194102 0.8824 hCV32055477 rs10779705 hCV8824394 rs1443929 0.510.519194102 0.5747 hCV32055477 rs10779705 hCV8824424 rs1058790 0.510.519194102 0.6417 hCV32055477 rs10779705 hCV8824425 rs1058791 0.510.519194102 0.62 hCV32055477 rs10779705 hCV8881145 rs1038008 0.510.519194102 1 hCV32055477 rs10779705 hCV8881146 rs1463054 0.510.519194102 1 hCV32055477 rs10779705 hCV8881157 rs1535158 0.510.519194102 1 hCV32055477 rs10779705 hCV8881161 rs926951 0.510.519194102 0.8759 hCV32055527 rs10864364 hCV11398434 rs1812457 0.510.494565781 0.7979 hCV32055527 rs10864364 hCV11398437 rs1817367 0.510.494565781 0.6548 hCV32055527 rs10864364 hCV11675962 rs10746481 0.510.494565781 0.8704 hCV32055527 rs10864364 hCV1188659 rs3820037 0.510.494565781 0.5447 hCV32055527 rs10864364 hCV1188660 rs6660137 0.510.494565781 0.5538 hCV32055527 rs10864364 hCV1188664 rs2765511 0.510.494565781 0.6126 hCV32055527 rs10864364 hCV1188665 rs2781060 0.510.494565781 0.6354 hCV32055527 rs10864364 hCV1188676 rs11121247 0.510.494565781 0.5538 hCV32055527 rs10864364 hCV1188731 rs4908514 0.510.494565781 1 hCV32055527 rs10864364 hCV1188735 rs10864366 0.510.494565781 1 hCV32055527 rs10864364 hCV12040675 rs2038904 0.510.494565781 0.6126 hCV32055527 rs10864364 hCV15882429 rs2289732 0.510.494565781 0.6247 hCV32055527 rs10864364 hCV15932991 rs2781067 0.510.494565781 0.6188 hCV32055527 rs10864364 hCV15932992 rs2781068 0.510.494565781 0.6121 hCV32055527 rs10864364 hCV27157507 rs6664000 0.510.494565781 1 hCV32055527 rs10864364 hCV27157524 rs6577531 0.510.494565781 0.9314 hCV32055527 rs10864364 hCV2741759 rs11121179 0.510.494565781 0.6713 hCV32055527 rs10864364 hCV27474399 rs3753275 0.510.494565781 0.5807 hCV32055527 rs10864364 hCV27884601 rs4908776 0.510.494565781 1 hCV32055527 rs10864364 hCV27958354 rs4908762 0.510.494565781 0.6717 hCV32055527 rs10864364 hCV28023091 rs4908773 0.510.494565781 1 hCV32055527 rs10864364 hCV29368919 rs4908513 0.510.494565781 1 hCV32055527 rs10864364 hCV2943451 rs902355 0.510.494565781 0.7098 hCV32055527 rs10864364 hCV2943853 rs301793 0.510.494565781 0.6247 hCV32055527 rs10864364 hCV2966436 rs11121174 0.510.494565781 0.6247 hCV32055527 rs10864364 hCV2966437 rs11580417 0.510.494565781 0.6247 hCV32055527 rs10864364 hCV2966441 rs6684863 0.510.494565781 0.6247 hCV32055527 rs10864364 hCV2966444 rs11121171 0.510.494565781 0.6727 hCV32055527 rs10864364 hCV29819064 rs6698079 0.510.494565781 0.7458 hCV32055527 rs10864364 hCV2987250 rs301810 0.510.494565781 0.5105 hCV32055527 rs10864364 hCV29873524 rs7533113 0.510.494565781 1 hCV32055527 rs10864364 hCV29873526 rs6697997 0.510.494565781 0.6952 hCV32055527 rs10864364 hCV29945430 rs7517436 0.510.494565781 1 hCV32055527 rs10864364 hCV30035535 rs7518204 0.510.494565781 1 hCV32055527 rs10864364 hCV30125699 rs4581300 0.510.494565781 0.6067 hCV32055527 rs10864364 hCV30143725 rs6690050 0.510.494565781 0.7437 hCV32055527 rs10864364 hCV30467730 rs6702457 0.510.494565781 0.8704 hCV32055527 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hCV498633 rs4968304 0.51 0.77061721 0.8598hCV341736 rs11653589 hCV7480314 rs3851799 0.51 0.77061721 1 hCV341736rs11653589 hCV9268384 rs7216950 0.51 0.77061721 0.8496 hCV342590 rs6030hCV15756374 rs2301515 0.51 0.9 0.9345 hCV342590 rs6030 hCV16175731rs2239852 0.51 0.9 0.9557 hCV342590 rs6030 hCV2481728 rs9332665 0.51 0.90.9593 hCV342590 rs6030 hCV27490260 rs3820060 0.51 0.9 0.9557 hCV342590rs6030 hCV30018856 rs6701330 0.51 0.9 1 hCV342590 rs6030 hCV340605rs1557572 0.51 0.9 0.9602 hCV342590 rs6030 hCV70275 rs4656687 0.51 0.90.9557 hCV342590 rs6030 hCV8919436 rs916438 0.51 0.9 0.9557 hCV342590rs6030 hCV8919438 rs1557570 0.51 0.9 0.9535 hCV370782 rs9841174hCV186893 rs2140364 0.51 0.9 0.9787 hCV370782 rs9841174 hCV26426702rs4955672 0.51 0.9 0.9788 hCV370782 rs9841174 hCV26426707 rs1104570 0.510.9 0.9582 hCV370782 rs9841174 hCV370768 rs9823383 0.51 0.9 0.9589hCV370782 rs9841174 hCV452184 rs6770577 0.51 0.9 0.92 hCV370782rs9841174 hCV82507 rs4129073 0.51 0.9 1 hCV435368 rs2812 hCV11611926rs12936766 0.51 0.9 1 hCV435368 rs2812 hCV11614606 rs2070783 0.51 0.90.9811 hCV435368 rs2812 hCV11614607 rs2070784 0.51 0.9 1 hCV435368rs2812 hCV25711 rs9913080 0.51 0.9 1 hCV435368 rs2812 hCV432101rs4968721 0.51 0.9 1 hCV435368 rs2812 hCV435365 rs6808 0.51 0.9 1hCV435368 rs2812 hCV454546 rs6504218 0.51 0.9 1 hCV435368 rs2812hCV481442 rs1122800 0.51 0.9 0.9442 hCV435368 rs2812 hCV502420 rs10503820.51 0.9 0.9625 hCV435368 rs2812 hCV502421 rs9902260 0.51 0.9 0.9625hCV435368 rs2812 hCV76415 rs9303469 0.51 0.9 1 hCV435368 rs2812 hCV76416rs9303470 0.51 0.9 1 hCV435368 rs2812 hCV76418 rs9892152 0.51 0.9 1hCV435368 rs2812 hCV9489827 rs1108592 0.51 0.9 1 hCV461035 rs7746448hCV11542275 rs3105258 0.51 0.9 0.9295 hCV461035 rs7746448 hCV11542286rs3125275 0.51 0.9 1 hCV461035 rs7746448 hCV11559368 rs6899649 0.51 0.90.962 hCV461035 rs7746448 hCV11560148 rs11966562 0.51 0.9 0.962hCV461035 rs7746448 hCV12026670 rs2047809 0.51 0.9 0.9435 hCV461035rs7746448 hCV238179 rs9370364 0.51 0.9 1 hCV461035 rs7746448 hCV238181rs11968305 0.51 0.9 0.9244 hCV461035 rs7746448 hCV238185 rs6914267 0.510.9 1 hCV461035 rs7746448 hCV26549031 rs6907460 0.51 0.9 0.9809hCV461035 rs7746448 hCV26549047 rs4518493 0.51 0.9 0.9226 hCV461035rs7746448 hCV26549113 rs4236122 0.51 0.9 0.9161 hCV461035 rs7746448hCV27953375 rs4712088 0.51 0.9 0.962 hCV461035 rs7746448 hCV27975017rs4398735 0.51 0.9 0.9435 hCV461035 rs7746448 hCV29161721 rs6915903 0.510.9 0.9309 hCV461035 rs7746448 hCV29161723 rs7766969 0.51 0.9 0.9435hCV461035 rs7746448 hCV30028095 rs10456690 0.51 0.9 0.9075 hCV461035rs7746448 hCV30136303 rs6914527 0.51 0.9 0.9415 hCV461035 rs7746448hCV30225897 rs9357829 0.51 0.9 0.9309 hCV461035 rs7746448 hCV358624rs4715508 0.51 0.9 0.9616 hCV472000 rs3002374 hCV114713 rs11145615 0.510.430305154 0.8909 hCV472000 rs3002374 hCV11760420 rs2498435 0.510.430305154 0.9002 hCV472000 rs3002374 hCV1463195 rs11145103 0.510.430305154 0.5214 hCV472000 rs3002374 hCV15978136 rs3002375 0.510.430305154 1 hCV472000 rs3002374 hCV15978147 rs2498420 0.51 0.4303051540.9002 hCV472000 rs3002374 hCV20899 rs4237276 0.51 0.430305154 0.8091hCV472000 rs3002374 hCV29033518 rs7021593 0.51 0.430305154 0.4946hCV472000 rs3002374 hCV29169220 rs4745688 0.51 0.430305154 0.8953hCV472000 rs3002374 hCV30442834 rs10481782 0.51 0.430305154 0.8903hCV472000 rs3002374 hCV320070 rs13286409 0.51 0.430305154 0.8094hCV472000 rs3002374 hCV446684 rs2252949 0.51 0.430305154 1 hCV472000rs3002374 hCV447339 rs2486450 0.51 0.430305154 0.8662 hCV472000rs3002374 hCV457907 rs3002376 0.51 0.430305154 0.9002 hCV472000rs3002374 hCV500457 rs7018554 0.51 0.430305154 0.9474 hCV472000rs3002374 hCV76127 rs9411192 0.51 0.430305154 0.9002 hCV472000 rs3002374hCV85712 rs946541 0.51 0.430305154 0.9474 hCV487868 rs6439132hCV11230071 rs12490685 0.51 0.9 1 hCV487868 rs6439132 hCV26427875rs6803892 0.51 0.9 1 hCV487868 rs6439132 hCV29665677 rs7631797 0.51 0.91 hCV487868 rs6439132 hCV30387127 rs7629705 0.51 0.9 0.9255 hCV529178rs301811 hCV11398434 rs1812457 0.51 0.536691312 0.8824 hCV529178rs301811 hCV11398437 rs1817367 0.51 0.536691312 0.8638 hCV529178rs301811 hCV11675962 rs10746481 0.51 0.536691312 0.8246 hCV529178rs301811 hCV1188731 rs4908514 0.51 0.536691312 0.7109 hCV529178 rs301811hCV1188735 rs10864366 0.51 0.536691312 0.6949 hCV529178 rs301811hCV15882429 rs2289732 0.51 0.536691312 0.7149 hCV529178 rs301811hCV25996298 rs7535752 0.51 0.536691312 0.58 hCV529178 rs301811hCV27157507 rs6664000 0.51 0.536691312 0.6949 hCV529178 rs301811hCV27157524 rs6577531 0.51 0.536691312 0.659 hCV529178 rs301811hCV2741759 rs11121179 0.51 0.536691312 0.6991 hCV529178 rs301811hCV27474399 rs3753275 0.51 0.536691312 0.5818 hCV529178 rs301811hCV27884601 rs4908776 0.51 0.536691312 0.7101 hCV529178 rs301811hCV27958354 rs4908762 0.51 0.536691312 1 hCV529178 rs301811 hCV28023091rs4908773 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV29368919rs4908513 0.51 0.536691312 0.7109 hCV529178 rs301811 hCV2943451 rs9023550.51 0.536691312 0.7442 hCV529178 rs301811 hCV2943853 rs301793 0.510.536691312 0.7149 hCV529178 rs301811 hCV2966436 rs11121174 0.510.536691312 0.7149 hCV529178 rs301811 hCV2966437 rs11580417 0.510.536691312 0.7149 hCV529178 rs301811 hCV2966441 rs6684863 0.510.536691312 0.7149 hCV529178 rs301811 hCV2966444 rs11121171 0.510.536691312 0.767 hCV529178 rs301811 hCV29819064 rs6698079 0.510.536691312 0.8488 hCV529178 rs301811 hCV2987250 rs301810 0.510.536691312 0.8909 hCV529178 rs301811 hCV29873524 rs7533113 0.510.536691312 0.7109 hCV529178 rs301811 hCV29873526 rs6697997 0.510.536691312 1 hCV529178 rs301811 hCV29945430 rs7517436 0.51 0.5366913120.6949 hCV529178 rs301811 hCV30035535 rs7518204 0.51 0.536691312 0.7098hCV529178 rs301811 hCV30125699 rs4581300 0.51 0.536691312 1 hCV529178rs301811 hCV30143725 rs6690050 0.51 0.536691312 0.8246 hCV529178rs301811 hCV30467730 rs6702457 0.51 0.536691312 0.8246 hCV529178rs301811 hCV3086930 rs6658881 0.51 0.536691312 0.8149 hCV529178 rs301811hCV3086932 rs7533442 0.51 0.536691312 0.8149 hCV529178 rs301811hCV3086950 rs4908771 0.51 0.536691312 0.8246 hCV529178 rs301811hCV3086961 rs6703577 0.51 0.536691312 0.8759 hCV529178 rs301811hCV3086971 rs6679948 0.51 0.536691312 0.8824 hCV529178 rs301811hCV3086972 rs6688329 0.51 0.536691312 0.8759 hCV529178 rs301811hCV3086998 rs7530863 0.51 0.536691312 1 hCV529178 rs301811 hCV3087000rs1463055 0.51 0.536691312 1 hCV529178 rs301811 hCV3087003 rs65775000.51 0.536691312 1 hCV529178 rs301811 hCV3087015 rs11121198 0.510.536691312 1 hCV529178 rs301811 hCV3087016 rs2297867 0.51 0.536691312 1hCV529178 rs301811 hCV32055284 rs12079653 0.51 0.536691312 0.6985hCV529178 rs301811 hCV32055470 rs6577506 0.51 0.536691312 0.8759hCV529178 rs301811 hCV32055474 rs10864359 0.51 0.536691312 0.8759hCV529178 rs301811 hCV32055477 rs10779705 0.51 0.536691312 0.8824hCV529178 rs301811 hCV32055527 rs10864364 0.51 0.536691312 0.6949hCV529178 rs301811 hCV32055548 rs11121197 0.51 0.536691312 1 hCV529178rs301811 hCV32055579 rs6577522 0.51 0.536691312 0.7106 hCV529178rs301811 hCV32055595 rs6577524 0.51 0.536691312 0.7109 hCV529178rs301811 hCV32055596 rs6577525 0.51 0.536691312 0.6949 hCV529178rs301811 hCV32055625 rs6678590 0.51 0.536691312 0.6074 hCV529178rs301811 hCV32055637 rs6577532 0.51 0.536691312 0.6401 hCV529178rs301811 hCV32055677 rs10864355 0.51 0.536691312 1 hCV529178 rs301811hCV529182 rs301800 0.51 0.536691312 0.7543 hCV529178 rs301811 hCV597227rs301809 0.51 0.536691312 1 hCV529178 rs301811 hCV597229 rs301785 0.510.536691312 1 hCV529178 rs301811 hCV877241 rs301788 0.51 0.5366913120.6991 hCV529178 rs301811 hCV8823713 rs1472228 0.51 0.536691312 0.6949hCV529178 rs301811 hCV8824288 rs910582 0.51 0.536691312 1 hCV529178rs301811 hCV8824394 rs1443929 0.51 0.536691312 0.6991 hCV529178 rs301811hCV8824424 rs1058790 0.51 0.536691312 0.767 hCV529178 rs301811hCV8824425 rs1058791 0.51 0.536691312 0.7538 hCV529178 rs301811hCV8881145 rs1038008 0.51 0.536691312 0.8824 hCV529178 rs301811hCV8881146 rs1463054 0.51 0.536691312 0.8271 hCV529178 rs301811hCV8881157 rs1535158 0.51 0.536691312 0.8824 hCV529178 rs301811hCV8881161 rs926951 0.51 0.536691312 1 hCV529706 rs428785 hCV1129216rs370850 0.51 0.9 0.9486 hCV529706 rs428785 hCV1129217 rs416905 0.51 0.90.9486 hCV529706 rs428785 hCV1129218 rs420742 0.51 0.9 0.9486 hCV529706rs428785 hCV11799502 rs392840 0.51 0.9 0.9486 hCV529706 rs428785hCV529701 rs422381 0.51 0.9 0.9523 hCV529706 rs428785 hCV529703 rs4517920.51 0.9 0.9523 hCV529706 rs428785 hCV529708 rs445784 0.51 0.9 0.9507hCV537525 rs197943 hCV15885004 rs2277614 0.51 0.550075489 0.6606hCV537525 rs197943 hCV2275251 rs197927 0.51 0.550075489 1 hCV537525rs197943 hCV2275252 rs197928 0.51 0.550075489 1 hCV537525 rs197943hCV2960488 rs197909 0.51 0.550075489 1 hCV537525 rs197943 hCV7451329rs197938 0.51 0.550075489 1 hCV549926 rs1057141 hCV16222565 rs23952690.51 0.9 0.921 hCV549926 rs1057141 hCV27015215 rs2071482 0.51 0.9 0.9603hCV549926 rs1057141 hCV2961762 rs12529313 0.51 0.9 1 hCV549926 rs1057141hCV2961763 rs12527715 0.51 0.9 1 hCV597227 rs301809 hCV11398434rs1812457 0.51 0.533875411 0.8824 hCV597227 rs301809 hCV11398437rs1817367 0.51 0.533875411 0.8638 hCV597227 rs301809 hCV11675962rs10746481 0.51 0.533875411 0.8248 hCV597227 rs301809 hCV1188731rs4908514 0.51 0.533875411 0.7112 hCV597227 rs301809 hCV1188735rs10864366 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV15882429rs2289732 0.51 0.533875411 0.7153 hCV597227 rs301809 hCV25996298rs7535752 0.51 0.533875411 0.5809 hCV597227 rs301809 hCV27157507rs6664000 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV27157524rs6577531 0.51 0.533875411 0.6596 hCV597227 rs301809 hCV2741759rs11121179 0.51 0.533875411 0.6996 hCV597227 rs301809 hCV27474399rs3753275 0.51 0.533875411 0.5827 hCV597227 rs301809 hCV27884601rs4908776 0.51 0.533875411 0.7103 hCV597227 rs301809 hCV27958354rs4908762 0.51 0.533875411 1 hCV597227 rs301809 hCV28023091 rs49087730.51 0.533875411 0.6952 hCV597227 rs301809 hCV29368919 rs4908513 0.510.533875411 0.7112 hCV597227 rs301809 hCV2943451 rs902355 0.510.533875411 0.7442 hCV597227 rs301809 hCV2943853 rs301793 0.510.533875411 0.7153 hCV597227 rs301809 hCV2966436 rs11121174 0.510.533875411 0.7153 hCV597227 rs301809 hCV2966437 rs11580417 0.510.533875411 0.7153 hCV597227 rs301809 hCV2966441 rs6684863 0.510.533875411 0.7153 hCV597227 rs301809 hCV2966444 rs11121171 0.510.533875411 0.7672 hCV597227 rs301809 hCV29819064 rs6698079 0.510.533875411 0.8488 hCV597227 rs301809 hCV2987250 rs301810 0.510.533875411 0.8909 hCV597227 rs301809 hCV29873524 rs7533113 0.510.533875411 0.7112 hCV597227 rs301809 hCV29873526 rs6697997 0.510.533875411 1 hCV597227 rs301809 hCV29945430 rs7517436 0.51 0.5338754110.6952 hCV597227 rs301809 hCV30035535 rs7518204 0.51 0.533875411 0.7101hCV597227 rs301809 hCV30125699 rs4581300 0.51 0.533875411 1 hCV597227rs301809 hCV30143725 rs6690050 0.51 0.533875411 0.8248 hCV597227rs301809 hCV30467730 rs6702457 0.51 0.533875411 0.8248 hCV597227rs301809 hCV3086930 rs6658881 0.51 0.533875411 0.815 hCV597227 rs301809hCV3086932 rs7533442 0.51 0.533875411 0.815 hCV597227 rs301809hCV3086950 rs4908771 0.51 0.533875411 0.8248 hCV597227 rs301809hCV3086961 rs6703577 0.51 0.533875411 0.8759 hCV597227 rs301809hCV3086971 rs6679948 0.51 0.533875411 0.8824 hCV597227 rs301809hCV3086972 rs6688329 0.51 0.533875411 0.8759 hCV597227 rs301809hCV3086998 rs7530863 0.51 0.533875411 1 hCV597227 rs301809 hCV3087000rs1463055 0.51 0.533875411 1 hCV597227 rs301809 hCV3087003 rs65775000.51 0.533875411 1 hCV597227 rs301809 hCV3087015 rs11121198 0.510.533875411 1 hCV597227 rs301809 hCV3087016 rs2297867 0.51 0.533875411 1hCV597227 rs301809 hCV32055284 rs12079653 0.51 0.533875411 0.6985hCV597227 rs301809 hCV32055470 rs6577506 0.51 0.533875411 0.8759hCV597227 rs301809 hCV32055474 rs10864359 0.51 0.533875411 0.8759hCV597227 rs301809 hCV32055477 rs10779705 0.51 0.533875411 0.8824hCV597227 rs301809 hCV32055527 rs10864364 0.51 0.533875411 0.6952hCV597227 rs301809 hCV32055548 rs11121197 0.51 0.533875411 1 hCV597227rs301809 hCV32055579 rs6577522 0.51 0.533875411 0.7109 hCV597227rs301809 hCV32055595 rs6577524 0.51 0.533875411 0.7112 hCV597227rs301809 hCV32055596 rs6577525 0.51 0.533875411 0.6952 hCV597227rs301809 hCV32055625 rs6678590 0.51 0.533875411 0.6074 hCV597227rs301809 hCV32055637 rs6577532 0.51 0.533875411 0.6408 hCV597227rs301809 hCV32055677 rs10864355 0.51 0.533875411 1 hCV597227 rs301809hCV529178 rs301811 0.51 0.533875411 1 hCV597227 rs301809 hCV529182rs301800 0.51 0.533875411 0.7545 hCV597227 rs301809 hCV597229 rs3017850.51 0.533875411 1 hCV597227 rs301809 hCV877241 rs301788 0.510.533875411 0.6996 hCV597227 rs301809 hCV8823713 rs1472228 0.510.533875411 0.6952 hCV597227 rs301809 hCV8824288 rs910582 0.510.533875411 1 hCV597227 rs301809 hCV8824394 rs1443929 0.51 0.5338754110.6996 hCV597227 rs301809 hCV8824424 rs1058790 0.51 0.533875411 0.7672hCV597227 rs301809 hCV8824425 rs1058791 0.51 0.533875411 0.754 hCV597227rs301809 hCV8881145 rs1038008 0.51 0.533875411 0.8824 hCV597227 rs301809hCV8881146 rs1463054 0.51 0.533875411 0.8271 hCV597227 rs301809hCV8881157 rs1535158 0.51 0.533875411 0.8824 hCV597227 rs301809hCV8881161 rs926951 0.51 0.533875411 1 hCV598677 rs5370 hCV15870027rs2071943 0.51 0.9 0.9736 hCV598677 rs5370 hCV7464888 rs1800543 0.51 0.90.9732 hCV598677 rs5370 hCV7464890 rs1476046 0.51 0.9 0.9736 hCV601946rs524802 hCV11467059 rs472226 0.51 0.9 0.9624 hCV601946 rs524802hCV25994206 rs3745770 0.51 0.9 0.9307 hCV601946 rs524802 hCV26697405rs547483 0.51 0.9 0.9624 hCV601946 rs524802 hCV26697407 rs496872 0.510.9 0.9649 hCV601946 rs524802 hCV27493801 rs3745768 0.51 0.9 0.9307hCV601946 rs524802 hCV30209952 rs10403679 0.51 0.9 0.9604 hCV601946rs524802 hCV601938 rs519551 0.51 0.9 0.9649 hCV601946 rs524802 hCV601939rs565721 0.51 0.9 0.9649 hCV601946 rs524802 hCV601940 rs474017 0.51 0.90.9624 hCV601946 rs524802 hCV601941 rs569371 0.51 0.9 0.9604 hCV601946rs524802 hCV601945 rs528504 0.51 0.9 0.9624 hCV601946 rs524802 hCV601954rs513406 0.51 0.9 0.9649 hCV601946 rs524802 hCV8712373 rs1667343 0.510.9 0.9639 hCV601946 rs524802 hCV8712515 rs826304 0.51 0.9 0.9624hCV601946 rs524802 hCV8712596 rs826303 0.51 0.9 0.9649 hCV601946rs524802 hCV8712603 rs826296 0.51 0.9 0.9642 hCV601946 rs524802hDV70773633 rs16971873 0.51 0.9 0.9649 hCV601961 rs568654 hCV11467027rs826262 0.51 0.9 1 hCV601961 rs568654 hCV32351622 rs519606 0.51 0.90.9649 hCV601961 rs568654 hCV601959 rs540451 0.51 0.9 1 hCV601961rs568654 hCV601962 rs544543 0.51 0.9 1 hCV601961 rs568654 hCV601964rs505717 0.51 0.9 1 hCV601961 rs568654 hCV601966 rs551717 0.51 0.9 1hCV601961 rs568654 hCV601969 rs510757 0.51 0.9 1 hCV601961 rs568654hCV601972 rs484001 0.51 0.9 1 hCV601961 rs568654 hCV8712620 rs8262900.51 0.9 1 hCV601961 rs568654 hCV8712646 rs1644711 0.51 0.9 1 hCV601962rs544543 hCV11467027 rs826262 0.51 0.9 1 hCV601962 rs544543 hCV32351622rs519606 0.51 0.9 0.9658 hCV601962 rs544543 hCV601959 rs540451 0.51 0.91 hCV601962 rs544543 hCV601961 rs568654 0.51 0.9 1 hCV601962 rs544543hCV601964 rs505717 0.51 0.9 1 hCV601962 rs544543 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hCV7442005 rs1538584 hCV11761223rs2309426 0.51 0.495145847 0.6079 hCV7442005 rs1538584 hCV11761237rs4329331 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV11761239rs4338173 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV11761245rs7043149 0.51 0.495145847 1 hCV7442005 rs1538584 hCV1844076 rs13395460.51 0.495145847 0.7161 hCV7442005 rs1538584 hCV20896 rs2309424 0.510.495145847 0.7161 hCV7442005 rs1538584 hCV25805877 rs3750549 0.510.495145847 0.6376 hCV7442005 rs1538584 hCV26566188 rs4375066 0.510.495145847 0.6691 hCV7442005 rs1538584 hCV26566190 rs3927676 0.510.495145847 0.6691 hCV7442005 rs1538584 hCV26566432 rs4076288 0.510.495145847 0.8185 hCV7442005 rs1538584 hCV26566437 rs4421408 0.510.495145847 0.6526 hCV7442005 rs1538584 hCV26566445 rs4339703 0.510.495145847 0.8065 hCV7442005 rs1538584 hCV27970553 rs5006364 0.510.495145847 0.8065 hCV7442005 rs1538584 hCV27996874 rs4745701 0.510.495145847 0.9644 hCV7442005 rs1538584 hCV29169289 rs6560585 0.510.495145847 0.6452 hCV7442005 rs1538584 hCV29577088 rs9314865 0.510.495145847 0.7161 hCV7442005 rs1538584 hCV29830130 rs10217168 0.510.495145847 0.7161 hCV7442005 rs1538584 hCV30172680 rs10122932 0.510.495145847 0.6452 hCV7442005 rs1538584 hCV30532761 rs10125494 0.510.495145847 0.6526 hCV7442005 rs1538584 hCV31363642 rs7862404 0.510.495145847 0.6403 hCV7442005 rs1538584 hCV31363652 rs10869961 0.510.495145847 0.6526 hCV7442005 rs1538584 hCV31363664 rs10869975 0.510.495145847 0.6889 hCV7442005 rs1538584 hCV31363697 rs7041781 0.510.495145847 0.6376 hCV7442005 rs1538584 hCV31364135 rs10781440 0.510.495145847 0.6798 hCV7442005 rs1538584 hCV31364138 rs7865373 0.510.495145847 0.6798 hCV7442005 rs1538584 hCV31364140 rs7467352 0.510.495145847 0.6455 hCV7442005 rs1538584 hCV31364141 rs11145460 0.510.495145847 0.6661 hCV7442005 rs1538584 hCV446682 rs2309427 0.510.495145847 0.6359 hCV7442005 rs1538584 hCV450641 rs10781456 0.510.495145847 0.6798 hCV7442005 rs1538584 hCV453560 rs10869992 0.510.495145847 0.6742 hCV7442005 rs1538584 hCV453561 rs10869993 0.510.495145847 0.6641 hCV7442005 rs1538584 hCV453562 rs10869994 0.510.495145847 0.6742 hCV7442005 rs1538584 hCV453563 rs10869997 0.510.495145847 0.678 hCV7442005 rs1538584 hCV456556 rs4076287 0.510.495145847 0.6673 hCV7442005 rs1538584 hCV463630 rs2486451 0.510.495145847 1 hCV7442005 rs1538584 hCV500456 rs10869976 0.51 0.4951458470.6857 hCV7442005 rs1538584 hCV7441996 rs867346 0.51 0.495145847 0.6831hCV7442005 rs1538584 hCV7442003 rs884428 0.51 0.495145847 0.6691hCV7442005 rs1538584 hCV7442004 rs884429 0.51 0.495145847 0.6691hCV7442005 rs1538584 hCV7482544 rs1416738 0.51 0.495145847 0.6798hCV7442005 rs1538584 hDV70840481 rs17062237 0.51 0.495145847 0.6742hCV7442005 rs1538584 hDV71162544 rs1416739 0.51 0.495145847 0.6567hCV7442005 rs1538584 hDV81101901 rs4745650 0.51 0.495145847 0.6526hCV7443062 rs897453 hCV7443053 rs1108579 0.51 0.9 0.9298 hCV7480314rs3851799 hCV16192346 rs2316758 0.51 0.769799979 1 hCV7480314 rs3851799hCV2592673 rs4968286 0.51 0.769799979 0.788 hCV7480314 rs3851799hCV2592715 rs3851792 0.51 0.769799979 1 hCV7480314 rs3851799 hCV26660327rs11869840 0.51 0.769799979 0.788 hCV7480314 rs3851799 hCV27899058rs4074249 0.51 0.769799979 0.8511 hCV7480314 rs3851799 hCV29195255rs8068715 0.51 0.769799979 1 hCV7480314 rs3851799 hCV29195260 rs38517980.51 0.769799979 1 hCV7480314 rs3851799 hCV2959464 rs3760377 0.510.769799979 0.788 hCV7480314 rs3851799 hCV2959466 rs6504622 0.510.769799979 0.788 hCV7480314 rs3851799 hCV2960484 rs11653838 0.510.769799979 0.8511 hCV7480314 rs3851799 hCV30299603 rs9889762 0.510.769799979 0.788 hCV7480314 rs3851799 hCV31479403 rs11079750 0.510.769799979 0.8526 hCV7480314 rs3851799 hCV341736 rs11653589 0.510.769799979 1 hCV7480314 rs3851799 hCV348972 rs11079747 0.51 0.7697999790.9616 hCV7480314 rs3851799 hCV473201 rs12950699 0.51 0.769799979 0.8598hCV7480314 rs3851799 hCV498633 rs4968304 0.51 0.769799979 0.8598hCV7480314 rs3851799 hCV9268384 rs7216950 0.51 0.769799979 0.8496hCV7490135 rs1805082 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0.9234 hCV783138 rs6046hCV783148 rs491098 0.51 0.9 0.9165 hCV7900503 rs3732379 hCV246550rs11713282 0.51 0.9 1 hCV7900503 rs3732379 hCV246551 rs11129819 0.51 0.91 hCV7900503 rs3732379 hCV403264 rs11711391 0.51 0.9 1 hCV7900503rs3732379 hCV7900501 rs11709600 0.51 0.9 1 hCV7900503 rs3732379hCV7900502 rs11710546 0.51 0.9 1 hCV7900503 rs3732379 hCV8759805rs1050592 0.51 0.9 1 hCV7910239 rs1541296 hCV3044407 rs2003149 0.51 0.91 hCV7910239 rs1541296 hCV3044408 rs1809319 0.51 0.9 1 hCV795441rs401502 hCV795442 rs375947 0.51 0.9 1 hCV795441 rs401502 hCV795446rs365179 0.51 0.9 0.9581 hCV795441 rs401502 hCV795454 rs429774 0.51 0.91 hCV795441 rs401502 hCV795455 rs382634 0.51 0.9 0.9103 hCV795441rs401502 hCV795459 rs376008 0.51 0.9 1 hCV795441 rs401502 hDV71612301rs17852635 0.51 0.9 1 hCV795442 rs375947 hCV795441 rs401502 0.51 0.9 1hCV795442 rs375947 hCV795446 rs365179 0.51 0.9 0.9552 hCV795442 rs375947hCV795454 rs429774 0.51 0.9 0.9795 hCV795442 rs375947 hCV795455 rs3826340.51 0.9 0.9059 hCV795442 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hCV8379452 rs4908781 hCV1188726 rs6698830 0.510.494607042 0.7147 hCV8379452 rs4908781 hCV1188747 rs4908511 0.510.494607042 0.7134 hCV8379452 rs4908781 hCV1188748 rs12028160 0.510.494607042 0.7134 hCV8379452 rs4908781 hCV1265858 rs11121194 0.510.494607042 0.4974 hCV8379452 rs4908781 hCV27157851 rs4480384 0.510.494607042 0.5249 hCV8379452 rs4908781 hCV29368911 rs6577513 0.510.494607042 0.5458 hCV8379452 rs4908781 hCV29855298 rs6690928 0.510.494607042 0.7355 hCV8379452 rs4908781 hCV29981708 rs7554486 0.510.494607042 0.5371 hCV8379452 rs4908781 hCV30233466 rs7513880 0.510.494607042 0.7147 hCV8379452 rs4908781 hCV30413939 rs6701331 0.510.494607042 0.4974 hCV8379452 rs4908781 hCV30413946 rs7537982 0.510.494607042 0.5249 hCV8379452 rs4908781 hCV3086941 rs7556169 0.510.494607042 0.526 hCV8379452 rs4908781 hCV3086945 rs6695867 0.510.494607042 0.5543 hCV8379452 rs4908781 hCV3086948 rs10864361 0.510.494607042 0.5552 hCV8379452 rs4908781 hCV3086949 rs11121212 0.510.494607042 0.5342 hCV8379452 rs4908781 hCV3086954 rs1463053 0.510.494607042 0.526 hCV8379452 rs4908781 hCV3086956 rs1463052 0.510.494607042 0.4974 hCV8379452 rs4908781 hCV3086959 rs7520025 0.510.494607042 0.5204 hCV8379452 rs4908781 hCV3086974 rs1318218 0.510.494607042 0.5323 hCV8379452 rs4908781 hCV3086976 rs11121204 0.510.494607042 0.5249 hCV8379452 rs4908781 hCV32055489 rs10864360 0.510.494607042 0.5342 hCV8379452 rs4908781 hCV32055498 rs4908507 0.510.494607042 0.5543 hCV8379452 rs4908781 hCV32055554 rs12024032 0.510.494607042 0.7134 hCV8379452 rs4908781 hCV32055587 rs10864367 0.510.494607042 0.7147 hCV8379452 rs4908781 hCV32055630 rs4908518 0.510.494607042 0.8302 hCV8379452 rs4908781 hCV32392515 rs4908505 0.510.494607042 0.5552 hCV8379452 rs4908781 hDV75072264 rs12403640 0.510.494607042 0.6803 hCV8379452 rs4908781 hDV77058075 rs4908506 0.510.494607042 0.526 hCV8420416 rs719909 hCV29251974 rs7905163 0.51 0.9 1hCV8420416 rs719909 hCV31659989 rs11185804 0.51 0.9 1 hCV8420416rs719909 hCV31659993 rs11185799 0.51 0.9 1 hCV8420416 rs719909hCV31659999 rs11185793 0.51 0.9 1 hCV8420416 rs719909 hCV31660000rs11185792 0.51 0.9 1 hCV8420416 rs719909 hCV31660001 rs11185791 0.510.9 1 hCV8420416 rs719909 hCV31660002 rs10881610 0.51 0.9 1 hCV8420416rs719909 hCV31660004 rs10881608 0.51 0.9 1 hCV8420416 rs719909hCV31660007 rs11185790 0.51 0.9 1 hCV8420416 rs719909 hCV31660048rs12777243 0.51 0.9 1 hCV8420416 rs719909 hCV8420325 rs11185780 0.51 0.91 hCV8420416 rs719909 hCV8420398 rs11185773 0.51 0.9 1 hCV8420416rs719909 hCV8870224 rs1075374 0.51 0.9 1 hCV8708473 rs1800469hCV11464030 rs1982072 0.51 0.9 1 hCV8708473 rs1800469 hCV15873885rs2241714 0.51 0.9 0.9776 hCV8708473 rs1800469 hCV15873886 rs22417150.51 0.9 0.9774 hCV8708473 rs1800469 hCV16193065 rs2317130 0.51 0.9 1hCV8709053 rs4880 hCV1362043 rs2842960 0.51 0.9 1 hCV8709053 rs4880hCV1362077 rs2842991 0.51 0.9 0.9625 hCV8709053 rs4880 hCV1362081rs2758319 0.51 0.9 0.9293 hCV8709053 rs4880 hCV16072287 rs2855116 0.510.9 0.9625 hCV8709053 rs4880 hCV16288770 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rs1748195 hCV32220469rs10889332 0.51 0.9 1 hCV9581635 rs1748195 hCV32220470 rs11207974 0.510.9 1 hCV9581635 rs1748195 hCV32220491 rs11577840 0.51 0.9 1 hCV9581635rs1748195 hCV32220495 rs11207969 0.51 0.9 1 hCV9581635 rs1748195hCV408090 rs1183260 0.51 0.9 1 hCV9581635 rs1748195 hCV445207 rs16275910.51 0.9 1 hCV9581635 rs1748195 hCV71419 rs2131925 0.51 0.9 1 hCV9581635rs1748195 hCV857102 rs624660 0.51 0.9 1 hCV9581635 rs1748195 hCV857103rs636497 0.51 0.9 0.979 hCV9581635 rs1748195 hCV857104 rs636523 0.51 0.90.959 hCV9581635 rs1748195 hCV857108 rs597078 0.51 0.9 1 hCV9581635rs1748195 hCV857109 rs597470 0.51 0.9 1 hCV9581635 rs1748195 hCV857110rs583609 0.51 0.9 1 hCV9581635 rs1748195 hCV857121 rs642845 0.51 0.9 1hCV9581635 rs1748195 hCV857122 rs656297 0.51 0.9 1 hCV9581635 rs1748195hCV857123 rs638305 0.51 0.9 1 hCV9581635 rs1748195 hCV857127 rs6311060.51 0.9 0.979 hCV9581635 rs1748195 hCV9508668 rs1781195 0.51 0.9 1hCV9581635 rs1748195 hCV9581062 rs998403 0.51 0.9 0.958 hCV9581635rs1748195 hCV9581551 rs1168040 0.51 0.9 0.9151 hCV9581635 rs1748195hCV9581570 rs1168036 0.51 0.9 1 hCV9581635 rs1748195 hCV9581571rs1002687 0.51 0.9 1 hCV9581635 rs1748195 hCV9581580 rs1168032 0.51 0.90.9789 hCV9581635 rs1748195 hCV9581581 rs1168030 0.51 0.9 1 hCV9581635rs1748195 hCV9581590 rs1168018 0.51 0.9 1 hCV9581635 rs1748195hCV9581606 rs1168022 0.51 0.9 1 hCV9581635 rs1748195 hCV9581615rs1748201 0.51 0.9 1 hCV9581635 rs1748195 hCV9581636 rs3850634 0.51 0.90.979 hCV9581635 rs1748195 hCV9581680 rs1748197 0.51 0.9 1 hCV9581635rs1748195 hCV9581691 rs1570694 0.51 0.9 0.979 hCV9581635 rs1748195hCV9583244 rs783291 0.51 0.9 1 hCV9581635 rs1748195 hCV9588770 rs10072050.51 0.9 1 hCV9581635 rs1748195 hCV9588793 rs1168009 0.51 0.9 0.9575hCV9581635 rs1748195 hCV9588794 rs1168010 0.51 0.9 0.9572 hCV9581635rs1748195 hCV9588829 rs1781212 0.51 0.9 1 hCV9581635 rs1748195hCV9588850 rs1168013 0.51 0.9 1 hCV9581635 rs1748195 hCV9588862 rs9950000.51 0.9 0.979 hCV9581635 rs1748195 hCV9588875 rs1168086 0.51 0.9 0.9551hCV9581635 rs1748195 hCV9588886 rs1168089 0.51 0.9 1 hCV9581635rs1748195 hCV9588930 rs1168099 0.51 0.9 1 hCV9581635 rs1748195hCV9588985 rs1168124 0.51 0.9 1 hCV9581635 rs1748195 hDV75176134rs1781221 0.51 0.9 1 hCV9588862 rs995000 hCV11864156 rs10889334 0.51 0.91 hCV9588862 rs995000 hCV11864162 rs1167998 0.51 0.9 0.9585 hCV9588862rs995000 hCV11865171 rs11208004 0.51 0.9 1 hCV9588862 rs995000hCV11865185 rs10789117 0.51 0.9 0.979 hCV9588862 rs995000 hCV11865201rs10159255 0.51 0.9 0.979 hCV9588862 rs995000 hCV12103105 rs1184865 0.510.9 0.9585 hCV9588862 rs995000 hCV12103127 rs1979722 0.51 0.9 0.9789hCV9588862 rs995000 hCV12103499 rs2029763 0.51 0.9 1 hCV9588862 rs995000hCV12103502 rs1168023 0.51 0.9 0.958 hCV9588862 rs995000 hCV1236535rs1168042 0.51 0.9 0.959 hCV9588862 rs995000 hCV149783 rs1168045 0.510.9 0.979 hCV9588862 rs995000 hCV16214290 rs2366638 0.51 0.9 0.959hCV9588862 rs995000 hCV1778957 rs3913007 0.51 0.9 1 hCV9588862 rs995000hCV1778958 rs634341 0.51 0.9 0.9558 hCV9588862 rs995000 hCV1778963rs10158897 0.51 0.9 0.979 hCV9588862 rs995000 hCV1778964 rs659656 0.510.9 1 hCV9588862 rs995000 hCV1778965 rs637723 0.51 0.9 0.9585 hCV9588862rs995000 hCV1918028 rs10157265 0.51 0.9 0.958 hCV9588862 rs995000hCV1918041 rs4587594 0.51 0.9 1 hCV9588862 rs995000 hCV1918054rs10889347 0.51 0.9 0.979 hCV9588862 rs995000 hCV2015148 rs11208007 0.510.9 0.9032 hCV9588862 rs995000 hCV25971202 rs10889335 0.51 0.9 0.9585hCV9588862 rs995000 hCV26412183 rs1748199 0.51 0.9 0.9577 hCV9588862rs995000 hCV26412184 rs11207990 0.51 0.9 0.9521 hCV9588862 rs995000hCV27320451 rs4350231 0.51 0.9 0.979 hCV9588862 rs995000 hCV27320465rs641540 0.51 0.9 0.9586 hCV9588862 rs995000 hCV29103721 rs6678483 0.510.9 0.979 hCV9588862 rs995000 hCV29103722 rs6675401 0.51 0.9 0.979hCV9588862 rs995000 hCV29103723 rs4329540 0.51 0.9 0.979 hCV9588862rs995000 hCV29647381 rs6690733 0.51 0.9 0.9585 hCV9588862 rs995000hCV29749081 rs10493322 0.51 0.9 1 hCV9588862 rs995000 hCV30224093rs7539035 0.51 0.9 0.979 hCV9588862 rs995000 hCV31145250 rs10889353 0.510.9 1 hCV9588862 rs995000 hCV31145255 rs11208000 0.51 0.9 0.9551hCV9588862 rs995000 hCV31145262 rs10889352 0.51 0.9 1 hCV9588862rs995000 hCV31145264 rs10789119 0.51 0.9 1 hCV9588862 rs995000hCV31145266 rs10789118 0.51 0.9 1 hCV9588862 rs995000 hCV31145267rs11485618 0.51 0.9 1 hCV9588862 rs995000 hCV31145269 rs6587980 0.51 0.90.979 hCV9588862 rs995000 hCV31145277 rs10889350 0.51 0.9 0.959hCV9588862 rs995000 hCV31145279 rs10889349 0.51 0.9 0.959 hCV9588862rs995000 hCV31145282 rs11207997 0.51 0.9 0.9169 hCV9588862 rs995000hCV31145290 rs12042319 0.51 0.9 1 hCV9588862 rs995000 hCV31145291rs11207995 0.51 0.9 0.9789 hCV9588862 rs995000 hCV31145298 rs112079920.51 0.9 1 hCV9588862 rs995000 hCV31145302 rs12116574 0.51 0.9 1hCV9588862 rs995000 hCV31145332 rs11207981 0.51 0.9 0.9538 hCV9588862rs995000 hCV3122390 rs1748200 0.51 0.9 0.959 hCV9588862 rs995000hCV316299 rs1168026 0.51 0.9 0.959 hCV9588862 rs995000 hCV316303rs1168031 0.51 0.9 0.9586 hCV9588862 rs995000 hCV32220452 rs120908860.51 0.9 1 hCV9588862 rs995000 hCV32220453 rs10889337 0.51 0.9 0.9585hCV9588862 rs995000 hCV32220467 rs10889333 0.51 0.9 1 hCV9588862rs995000 hCV32220469 rs10889332 0.51 0.9 0.979 hCV9588862 rs995000hCV32220470 rs11207974 0.51 0.9 0.959 hCV9588862 rs995000 hCV32220491rs11577840 0.51 0.9 0.9586 hCV9588862 rs995000 hCV32220495 rs112079690.51 0.9 0.979 hCV9588862 rs995000 hCV408090 rs1183260 0.51 0.9 0.9566hCV9588862 rs995000 hCV445207 rs1627591 0.51 0.9 0.959 hCV9588862rs995000 hCV71419 rs2131925 0.51 0.9 0.959 hCV9588862 rs995000 hCV857102rs624660 0.51 0.9 0.979 hCV9588862 rs995000 hCV857103 rs636497 0.51 0.90.9577 hCV9588862 rs995000 hCV857104 rs636523 0.51 0.9 1 hCV9588862rs995000 hCV857108 rs597078 0.51 0.9 0.958 hCV9588862 rs995000 hCV857109rs597470 0.51 0.9 0.959 hCV9588862 rs995000 hCV857110 rs583609 0.51 0.90.979 hCV9588862 rs995000 hCV857121 rs642845 0.51 0.9 0.958 hCV9588862rs995000 hCV857122 rs656297 0.51 0.9 0.979 hCV9588862 rs995000 hCV857123rs638305 0.51 0.9 0.959 hCV9588862 rs995000 hCV857127 rs631106 0.51 0.90.9577 hCV9588862 rs995000 hCV9508668 rs1781195 0.51 0.9 0.979hCV9588862 rs995000 hCV9581062 rs998403 0.51 0.9 1 hCV9588862 rs995000hCV9581570 rs1168036 0.51 0.9 1 hCV9588862 rs995000 hCV9581571 rs10026870.51 0.9 0.959 hCV9588862 rs995000 hCV9581580 rs1168032 0.51 0.9 0.958hCV9588862 rs995000 hCV9581581 rs1168030 0.51 0.9 0.959 hCV9588862rs995000 hCV9581590 rs1168018 0.51 0.9 0.9789 hCV9588862 rs995000hCV9581606 rs1168022 0.51 0.9 0.9558 hCV9588862 rs995000 hCV9581615rs1748201 0.51 0.9 0.9789 hCV9588862 rs995000 hCV9581635 rs1748195 0.510.9 0.979 hCV9588862 rs995000 hCV9581636 rs3850634 0.51 0.9 1 hCV9588862rs995000 hCV9581680 rs1748197 0.51 0.9 0.959 hCV9588862 rs995000hCV9581691 rs1570694 0.51 0.9 1 hCV9588862 rs995000 hCV9583244 rs7832910.51 0.9 0.959 hCV9588862 rs995000 hCV9588770 rs1007205 0.51 0.9 0.959hCV9588862 rs995000 hCV9588793 rs1168009 0.51 0.9 0.9365 hCV9588862rs995000 hCV9588794 rs1168010 0.51 0.9 0.936 hCV9588862 rs995000hCV9588829 rs1781212 0.51 0.9 0.959 hCV9588862 rs995000 hCV9588850rs1168013 0.51 0.9 0.979 hCV9588862 rs995000 hCV9588875 rs1168086 0.510.9 0.9551 hCV9588862 rs995000 hCV9588886 rs1168089 0.51 0.9 0.979hCV9588862 rs995000 hCV9588930 rs1168099 0.51 0.9 0.979 hCV9588862rs995000 hCV9588985 rs1168124 0.51 0.9 0.959 hCV9588862 rs995000hDV75176134 rs1781221 0.51 0.9 0.959 hCV9596963 rs6115 hCV9596972 rs61120.51 0.9 0.9634 hCV9604851 rs1805002 hDV77041261 rs4758402 0.51 0.9 1hDV70661573 rs16875009 hCV2928259 rs6867948 0.51 0.409905558 0.656hDV70661573 rs16875009 hCV2928266 rs11742566 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928267 rs12517136 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928268 rs11134096 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928269 rs11134097 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928270 rs12515050 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928271 rs12520783 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928278 rs12522919 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928283 rs12518805 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928284 rs12518833 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928288 rs11748003 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928289 rs7446660 0.51 0.409905558 0.4246hDV70661573 rs16875009 hCV2928293 rs12517784 0.51 0.409905558 1hDV70661573 rs16875009 hCV2928295 rs1428025 0.51 0.409905558 0.4246hDV70661573 rs16875009 hCV2928306 rs1428024 0.51 0.409905558 1hDV70661573 rs16875009 hCV32226945 rs12521996 0.51 0.409905558 1hDV70661573 rs16875009 hCV32226946 rs12517751 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703783 rs16874942 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703799 rs16874970 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703820 rs16874994 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703822 rs16874998 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703832 rs16875012 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703845 rs16875031 0.51 0.409905558 0.8803hDV70661573 rs16875009 hDV70703846 rs16875033 0.51 0.409905558 1hDV70661573 rs16875009 hDV70703851 rs16875038 0.51 0.409905558 1hDV70938014 rs17321515 hCV11593303 rs2980871 0.51 0.9 0.9634 hDV70938014rs17321515 hCV12004940 rs2001844 0.51 0.9 1 hDV70938014 rs17321515hCV15883779 rs2980869 0.51 0.9 1 hDV70938014 rs17321515 hCV15883790rs2980875 0.51 0.9 0.9619 hDV70938014 rs17321515 hCV15954624 rs29540220.51 0.9 0.9634 hDV70938014 rs17321515 hCV15954645 rs2954029 0.51 0.90.9634 hDV70938014 rs17321515 hCV26372062 rs2980856 0.51 0.9 1hDV70938014 rs17321515 hCV26372064 rs2980855 0.51 0.9 1 hDV70938014rs17321515 hCV26372065 rs2980854 0.51 0.9 1 hDV70938014 rs17321515hCV26372066 rs2980853 0.51 0.9 1 hDV70938014 rs17321515 hCV26372069rs2980882 0.51 0.9 1 hDV70938014 rs17321515 hCV29719123 rs6982636 0.510.9 1 hDV70938014 rs17321515 hCV309481 rs2954019 0.51 0.9 1 hDV70938014rs17321515 hCV469160 rs2954031 0.51 0.9 0.9279 hDV70938014 rs17321515hCV85515 rs10808546 0.51 0.9 0.9064 hDV70973697 rs17593921 hDV70715540rs16891266 0.51 0.612665933 0.6234 hDV70977122 rs17616652 hCV11627552rs2316667 0.51 0.442542981 0.7059 hDV70977122 rs17616652 hCV1718966rs4968305 0.51 0.442542981 0.7074 hDV70977122 rs17616652 hCV26683367rs9894300 0.51 0.442542981 0.6395 hDV70977122 rs17616652 hCV26683368rs2004580 0.51 0.442542981 0.6405 hDV70977122 rs17616652 hCV29195269rs7221042 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hCV30515746rs10491149 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hCV31479223rs11570460 0.51 0.442542981 0.7356 hDV70977122 rs17616652 hCV31479380rs4520895 0.51 0.442542981 0.642 hDV70977122 rs17616652 hCV7451110rs1515754 0.51 0.442542981 0.7356 hDV70977122 rs17616652 hCV9268649rs16941168 0.51 0.442542981 0.5852 hDV70977122 rs17616652 hDV70590478rs9897338 0.51 0.442542981 0.642 hDV70977122 rs17616652 hDV70751669rs16941353 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hDV70751822rs16941584 0.51 0.442542981 0.7366 hDV70977122 rs17616652 hDV70975179rs17603901 0.51 0.442542981 0.6562 hDV70977122 rs17616652 hDV70987720rs17676978 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hDV75285090rs2667804 0.51 0.442542981 0.7074

TABLE 7 Association test results from two MI case-control studies GeneRisk CCF UCSF SNP Symbol Allele OR (95% CI) P Strata Model OR (95% CI) PStrata Model Tested* rs6668968 AQP10 A 1.29 (1.07-1.57) 0.008 ALL add1.16 (1.00-1.35) 0.050 ALL add † rs13078881 BTD G 2.95 (1.27-6.89) 0.012F add 1.73 (0.94-3.20) 0.079 F add † rs1051038 COG2 A 1.23 (0.99-1.53)0.063 ALL add 1.19 (0.97-1.46) 0.088 ALL rec † rs2035029 DCC G 1.35(1.04-1.76) 0.024 ALL dom 1.22 (1.00-1.50) 0.053 ALL dom † Chr17:74022684 DNAHL1 C 1.85 (0.95-3.63) 0.072 ALL add 1.96 (0.97-3.94) 0.060M add † rs34639489 ERV3 C 1.16 (0.98-1.38) 0.092 ALL add 1.13(0.98-1.30) 0.086 ALL add † rs4149965 EXO1 A 1.34 (1.03-1.73) 0.028 Madd 1.38 (1.10-1.73) 0.005 M add † rs2304024 FAT2 G 1.20 (0.97-1.50)0.097 ALL add 1.23 (1.04-1.46) 0.019 ALL add † rs12915 GALNAC4S- C 1.17(0.98-1.40) 0.080 ALL add 1.13 (0.98-1.30) 0.088 ALL add † 6ST rs197922GOSR2 A 1.29 (0.98-1.70) 0.071 F add 1.17 (1.01-1.34) 0.032 ALL add †rs2296434 HPS1 G 1.39 (1.01-1.90) 0.042 ALL add 1.34 (0.96-1.85) 0.082 Madd † rs1060446 HPSE2 C 1.27 (1.07-1.50) 0.006 ALL add 1.14 (1.00-1.31)0.052 ALL add † rs3739998 KIAA1462 G 1.26 (0.96-1.65) 0.093 F add 1.30(1.06-1.61) 0.012 F add † rs3110234 LIFR T 1.19 (0.96-1.46) 0.066 ALLgen 1.17 (0.99-1.39) 0.070 ALL gen † rs28756981 MLH3 T 3.23 (1.10-9.50)0.033 M add 4.58 (1.28-16.33) 0.019 M add † rs11051410 none G 1.22(1.01-1.46) 0.038 ALL add 1.16 (1.00-1.34) 0.045 ALL add † rs1023899none A 1.82 (1.19-2.78) 0.006 M add 1.40 (0.99-1.97) 0.059 M add †rs2959189 none G 1.59 (1.10-2.30) 0.014 ALL dom 1.27 (0.97-1.67) 0.085ALL dom † rs10622 none T 1.27 (0.98-1.65) 0.066 ALL rec 1.28 (1.04-1.57)0.018 ALL rec † rs7736962 none A 1.30 (1.01-1.67) 0.044 ALL rec 1.30(0.98-1.72) 0.064 M rec † rs4706769 none T 1.17 (0.99-1.39) 0.067 ALLadd 1.26 (1.04-1.53) 0.017 M add † rs3196714 ODAM T 1.45 (0.95-2.23)0.085 ALL dom 1.32 (0.95-1.82) 0.095 ALL dom † rs1151640 OR13G1 C 1.34(1.12-1.60) 0.001 ALL add 1.16 (1.01-1.33) 0.042 ALL add † rs11219508OR8G2 C 1.45 (0.98-2.15) 0.065 F dom 1.34 (1.01-1.78) 0.042 F dom †rs2278586 OXER1 C 1.37 (0.98-1.91) 0.063 F add 1.35 (1.06-1.72) 0.014 Fadd † rs2970871 PPARGC1A C 1.17 (0.98-1.40) 0.080 ALL add 1.26(0.98-1.61) 0.072 ALL dom † rs3750533 PRPF4 T 1.21 (0.97-1.52) 0.099 Madd 1.20 (0.98-1.47) 0.076 M add † rs2297322 SLC15A1 C 1.44 (1.02-2.04)0.037 M add 1.32 (0.98-1.76) 0.066 M add † rs2072549 SLC7A4 A 1.24(1.00-1.53) 0.046 ALL add 1.17 (0.98-1.39) 0.079 ALL add † rs1785934STATIP1 C 1.36 (0.98-1.88) 0.067 M dom 1.25 (1.02-1.53) 0.029 ALL dom †rs11735477 TKTL2 A 1.35 (1.04-1.75) 0.026 ALL dom 1.28 (0.95-1.72) 0.098M dom † rs1042589 TPO C 1.24 (0.99-1.56) 0.061 M add 1.19 (1.04-1.36)0.011 ALL add † rs1108225 TRPM3 A 1.23 (1.00-1.50) 0.048 ALL add 1.23(1.05-1.45) 0.012 ALL add † rs10083789 USP31 A 1.22 (1.01-1.46) 0.036ALL add 1.20 (1.04-1.39) 0.012 ALL add † rs35305327 WDR31 A 3.64(1.04-12.75) 0.043 ALL add 2.48 (1.13-5.46) 0.023 ALL add † rs1465789ZNF132 G 1.21 (0.98-1.50) 0.080 M add 1.19 (0.99-1.43) 0.071 M add †rs2017252 ZNF273 A 1.17 (0.99-1.39) 0.066 ALL add 1.18 (1.03-1.35) 0.017ALL add † rs2884554 ZNF714 G 1.25 (0.97-1.61) 0.079 ALL add 1.19(0.99-1.44) 0.063 ALL add † rs3027309 ALOX12B T 1.27 (1.02-1.59) 0.035ALL add 1.18 (0.99-1.41) 0.068 ALL add ‡ rs2296436 HPS1 T 1.36(0.99-1.85) 0.054 ALL add 1.32 (0.95-1.82) 0.095 M add ‡ rs1042636 CASRG 1.64 (0.94-2.86) 0.082 F add 1.30 (1.00-1.70) 0.047 ALL add ‡rs1376251 TAS2R50 C 1.26 (1.05-1.52) 0.014 ALL add 1.23 (1.07-1.41)0.004 ALL add ‡ rs12102203 RC3 G 1.38 (1.15-1.64) <0.001 ALL add 1.18(1.03-1.35) 0.014 ALL add ‡ rs2286394 WDR55 T 1.24 (1.01-1.53) 0.037 ALLadd 1.18 (1.00-1.39) 0.044 ALL add ‡ rs2307469 EIF2AK2 C 1.48(0.95-2.32) 0.086 ALL add 1.71 (1.17-2.51) 0.006 ALL add ‡ rs3213646MGC16943 C 1.22 (0.97-1.53) 0.092 M add 1.18 (0.98-1.43) 0.076 M add ‡rs5985 F13A1 A 1.23 (1.01-1.51) 0.040 ALL add 1.21 (1.04-1.41) 0.013 ALLadd ‡ Chr2: 37081301 KIAA1414 G 1.54 (1.07-2.20) 0.019 ALL add 1.59(1.19-2.12) 0.002 ALL add ‡§ rs1042164 IER2 T 1.31 (1.03-1.69) 0.028 ALLadd 1.22 (0.98-1.52) 0.070 ALL add ‡ rs6761276 IL1F10 T 1.25 (1.03-1.50)0.020 ALL add 1.23 (1.07-1.41) 0.004 ALL add ‡ rs6743376 IL1F10 C 1.24(1.03-1.49) 0.024 ALL add 1.22 (1.06-1.40) 0.006 ALL add ‡ rs943133LOC391102 A 1.24 (1.02-1.51) 0.030 ALL add 1.19 (1.02-1.38) 0.023 ALLadd ‡ rs3130210 LOC442203 T 1.24 (1.01-1.53) 0.037 ALL add 1.29(1.09-1.52) 0.002 ALL add ‡ rs3129196 LOC442203 A 1.25 (1.02-1.53) 0.035ALL add 1.29 (1.10-1.52) 0.002 ALL add ‡ rs12510359 PALLD G 1.26(1.05-1.51) 0.011 ALL add 1.22 (1.07-1.41) 0.004 ALL add ‡ rs7439293PALLD A 1.21 (1.01-1.46) 0.042 ALL add 1.22 (1.06-1.40) 0.006 ALL add‡|| rs3798220 LPA C 4.71 (0.00-0.00) <0.001 ALL add 1.76 (0.00-0.00)0.014 ALL add ‡ rs10082504 MKI67 C 1.38 (1.03-1.84) 0.034 ALL add 1.26(1.01-1.59) 0.043 ALL add ‡ rs4750685 MKI67 G 1.33 (0.98-1.81) 0.069 ALLadd 1.26 (1.00-1.59) 0.054 ALL add ‡¶ rs3900940 MYH15 C 0.32 (0.97-1.78)0.078 F add 1.31 (1.05-1.63) 0.015 F add ‡|| rs12145360 MYOM3 A 1.36(0.98-1.90) 0.069 M add 1.59 (1.22-2.07) 0.001 M add ‡ rs12684749 NFIB A2.59 (1.39-4.82) 0.003 ALL add 1.36 (0.95-1.96) 0.097 ALL add ‡rs3808117 GRM8 T 1.58 (1.26-1.98) 0.000 ALL add 1.21 (1.02-1.44) 0.026ALL add ‡ rs2277838 P2RXL1 A 1.27 (1.02-1.58) 0.032 ALL add 1.21(1.02-1.44) 0.032 ALL add ‡ rs3813135 PGLYRP2 C 1.25 (0.96-1.63) 0.095ALL dom 1.27 (1.04-1.55) 0.020 ALL dom ‡ rs211070 PRKG1 G 1.71(1.06-2.76) 0.029 ALL add 1.42 (1.03-1.97) 0.034 ALL add ‡ rs619203 ROS1C 1.31 (1.06-1.61) 0.012 ALL add 1.30 (1.11-1.52) 0.001 ALL add ‡rs529038 ROS1 T 1.31 (1.07-1.61) 0.010 ALL add 1.31 (1.12-1.53) 0.001ALL add ‡ rs17090921 SERPINA9 A 2.31 (1.14-4.66) 0.019 F rec 1.50(0.94-2.38) 0.087 F rec ‡ rs11628722 SERPINA9 G 1.26 (0.99-1.60) 0.058ALL add 1.17 (0.98-1.39) 0.091 ALL add ‡ rs4747647 TAF3 A 1.22(1.02-1.47) 0.033 ALL add 1.15 (1.00-1.32) 0.056 ALL add ‡ rs1010 VAMP8C 1.36 (1.13-1.64) 0.001 ALL add 1.25 (1.09-1.43) 0.002 ALL add ‡||rs6685323 AQP10 T 1.33 (1.10-1.61) 0.003 ALL add 1.19 (1.03-1.38) 0.020ALL add # rs6480771 DUSP13 G 1.20 (1.01-1.43) 0.084 ALL gen 1.07(0.93-1.23) 0.063 ALL gen # rs887 FLJ42562 G 1.21 (1.01-1.46) 0.040 ALLadd 1.17 (1.01-1.35) 0.032 ALL add # rs28711149 OR13G1 T 1.21(1.01-1.45) 0.038 ALL add 1.29 (0.97-1.72) 0.083 ALL dom # rs1126799 TPOC 1.16 (0.98-1.37) 0.091 ALL add 1.22 (0.99-1.51) 0.064 ALL rec # SNP,single nucleotide polymorphism; CCF, Cleveland Clinic Foundation; USCF,University of California, San Francisco; OR, odds ratio; CI, confidenceinterval; *This column indicates the location of published results forthe testing of the association for each SNP and incident coronary heartdisease in the Atherosclerosis Risk in Communities cohort.; † Onlinesupplemental table II, Meyer et al., “A GOSR2 variant is associated withhypertension”, Hypertension, 2008; ‡ Morrison et al.³³; § previouslyreported as Chr2: 37139448 in build 35; || Bare et al.³⁴; ¶ previouslyreported as Chr10: 129793007 in build 35; # not reported because goodmultiplex assays could not be made

TABLE 8 Descriptive information by race and GOSR2 genotype Whites (N =9,861) Blacks (N = 3,528) ArgArg LysArg LysLys ArgArg LysArg LysLys (n =4,264) (n = 4,398) (n = 1,199) P* (n = 1,698) (n = 1,494) (n = 336) P*Mean ± SD Age, y  54 ± 5.7  54 ± 5.7  54 ± 5.8 0.26  53 ± 5.7  53 ± 5.9 54 ± 5.8 0.01 SBP (mmHg)^(†) 115.5 ± 15.6  116.7 ± 16.1  116.6 ± 16.0 <0.01 125.4 ± 19.6  125.5 ± 20.4  128.5 ± 21.2  0.15 DBP (mmHg)^(†) 70.5± 9.6  70.9 ± 9.8  71.0 ± 9.9  0.09 78.5 ± 11.3 78.1 ± 12.0 79.2 ± 12.30.96 Waist circumference (cm) 95.5 ± 13.4 96.4 ± 13.5 95.8 ± 13.2 0.0599.0 ± 15.5 98.8 ± 14.8 99.2 ± 14.6 0.88 Ln (triglycerides) (mmol/L)^(‡)0.27 ± 0.50 0.29 ± 0.51 0.28 ± 0.53 0.15 0.09 ± 0.46 0.09 ± 0.48 0.10 ±0.45 0.80 HDL cholesterol (mmol/L) 1.3 ± 0.4 1.3 ± 0.4 1.3 ± 0.4 0.961.4 ± 0.4 1.4 ± 0.5 1.4 ± 0.5 0.13 Glucose (mmol/L)^(§) 5.5 ± 0.5 5.5 ±0.5 5.5 ± 0.5 0.93 5.5 ± 0.6 5.5 ± 0.5 5.4 ± 0.6 0.15 CA IMT (mm) 0.73 ±0.18 0.74 ± 0.18 0.74 ± 0.17 0.02 0.74 ± 0.16 0.73 ± 0.16 0.75 ± 0.170.60 No. (%) Male 1,952 (46) 1,983 (45) 551 (46) 0.77 643 (38) 542 (36)116 (35) 0.42 Hypertension 1,012 (24) 1,181 (27) 314 (26) <0.01 926 (55)797 (53) 186 (56) 0.66 Diabetes  327 (8)  375 (9) 105 (9)  0.26 308 (19)261 (18)  65 (20) 0.68 SD, standard deviation; CA, carotid artery; IMT,intima media thickness; *P values are for the differences betweengenotypes (F-test for continuous variables or X² test for categoricalvariables); ^(†)Excluding participants taking anti-hypertensivemedications; ^(‡)among those who fasted for at least 8 hours; ^(§)amongnondiabetics who fasted for at least 8 hours

TABLE 9 OR and 95% CI for the association between GOSR2 (Lys67Arg,rs197922), hypertension, and carotid artery thickness Whites (N = 9,822)Blacks (N = 3,513) n OR (95% CI)* P^(‡) n OR (95% CI)* P^(‡)Hypertension 2,506 1.09 (1.02 to 1.17) 0.01 1,909 0.96 (0.87 to 1.07)0.47 Elevated SBP (≧75% tile) 2,531 1.08 (1.00 to 1.15)^(†) 0.04 9091.04 (0.92 to 1.17)^(†) 0.52 Elevated DBP (≧75% tile) 2,606 1.08 (1.01to 1.16)^(†) 0.02 904 1.03 (0.92 to 1.16)^(†) 0.57 Thick CA IMT^(§)(≧75% tile) 2,284 1.09 (1.01 to 1.17) 0.02 830 0.99 (0.88 to 1.13) 0.92OR, odds ratio; CI, confidence interval; n, number of affected; SBP,systolic blood pressure; DBP, diastolic blood pressure; CA, carotidartery; IMT, intima media thickness; *adjusted for gender and age atbaseline; ^(†)additionally adjusted for anti-hypertensive medicationuse; ^(‡)P is Wald test p-value; ^(§)N = 9,302 whites and 3,146 blacks

TABLE 10 UCSF1 Case Control Case Control Allele Allele marker rs GeneRiskAllele NonRiskAllele Samples** Samples** Freq* Freq* OR* OR95L*hCV11623551 rs8073829 LOC731128 C T 754 971 0.88 0.85 1.28 1.05hCV15885004 rs2277614 LRRC37A2 A G 753 970 0.04 0.03 1.47 1.02hCV2275263 rs197912 LRRC37A2 A T 754 972 0.38 0.35 1.17 1.02 hCV2275272rs197920 GOSR2 T C 721 861 0.32 0.29 1.15 0.99 hCV2275276 rs197925 GOSR2A G 716 862 0.41 0.38 1.15 1.00 hCV2592654 rs1662577 LRRC37A2 A C 753970 0.40 0.37 1.13 0.99 hCV2592662 rs2191033 GOSR2 G A 715 859 0.41 0.381.16 1.01 hCV2592715 rs3851792 LRRC37A2 A T 715 859 0.57 0.54 1.14 0.98hCV2592759 rs8080126 LRRC37A2 A C 754 973 0.73 0.71 1.14 0.98hCV26660340 rs4968246 LRRC37A2 G C 754 973 0.40 0.36 1.15 1.00hCV26683367 rs9894300 LOC731128 G C 754 973 0.88 0.85 1.28 1.05hCV26683368 rs2004580 LOC731128 C T 755 973 0.88 0.85 1.26 1.04hCV29195255 rs8068715 LRRC37A2 C A 723 858 0.57 0.54 1.14 0.99hCV29195260 rs3851798 LRRC37A2 A G 725 863 0.57 0.54 1.15 1.00hCV2960489 rs3785889 GOSR2 G A 719 861 0.51 0.47 1.16 1.00 hCV31466171rs10853085 LRRC37A2 G A 718 863 0.40 0.37 1.15 0.99 hCV341736 rs11653589LRRC37A2 T C 724 860 0.58 0.54 1.16 1.00 hCV537525 rs197943 LRRC37A2 C A754 971 0.06 0.04 1.45 1.07 hCV7451269 rs1662594 LRRC37A2 A G 725 8610.39 0.36 1.13 0.98 hCV7480314 rs3851799 LRRC37A2 C T 724 862 0.58 0.541.14 0.99 hDV70751699 rs16941393 LRRC37A2 A T 755 973 0.92 0.90 1.220.96 hDV70751704 rs16941401 LRRC37A2 T A 752 972 0.92 0.90 1.23 0.97hDV70751706 rs16941404 LRRC37A2 G C 754 968 0.20 0.18 1.17 0.99hDV70977122 rs17616652 LRRC37A2 A G 752 973 0.92 0.89 1.46 1.16r{circumflex over ( )}2 with hCV2275273 marker rs Gene RiskAlleleNonRiskAllele OR95U* P_value Strata Model (GOSR2) hCV11623551 rs8073829LOC731128 C T 1.56 0.014 AllvsAll add 0.043 hCV15885004 rs2277614LRRC37A2 A G 2.13 0.041 AllvsAll add 0.061 hCV2275263 rs197912 LRRC37A2A T 1.35 0.026 AllvsAll add 0.851 hCV2275272 rs197920 GOSR2 T C 1.330.076 AllvsAll add 0.82 hCV2275276 rs197925 GOSR2 A G 1.33 0.057AllvsAll add 0.737 hCV2592654 rs1662577 LRRC37A2 A C 1.30 0.076 AllvsAlladd 0.806 hCV2592662 rs2191033 GOSR2 G A 1.34 0.041 AllvsAll add 0.739hCV2592715 rs3851792 LRRC37A2 A T 1.31 0.085 AllvsAll add 0.252hCV2592759 rs8080126 LRRC37A2 A C 1.32 0.095 AllvsAll add 0.015hCV26660340 rs4968246 LRRC37A2 G C 1.32 0.045 AllvsAll add 0.541hCV26683367 rs9894300 LOC731128 G C 1.56 0.014 AllvsAll add 0.043hCV26683368 rs2004580 LOC731128 C T 1.54 0.019 AllvsAll add 0.044hCV29195255 rs8068715 LRRC37A2 C A 1.32 0.066 AllvsAll add 0.254hCV29195260 rs3851798 LRRC37A2 A G 1.33 0.056 AllvsAll add 0.254hCV2960489 rs3785889 GOSR2 G A 1.33 0.044 AllvsAll add 0.512 hCV31466171rs10853085 LRRC37A2 G A 1.32 0.062 AllvsAll add 0.79 hCV341736rs11653589 LRRC37A2 T C 1.34 0.046 AllvsAll add 0.25 hCV537525 rs197943LRRC37A2 C A 1.97 0.016 AllvsAll add 0.028 hCV7451269 rs1662594 LRRC37A2A G 1.31 0.088 AllvsAll add 0.796 hCV7480314 rs3851799 LRRC37A2 C T 1.320.068 AllvsAll add 0.253 hDV70751699 rs16941393 LRRC37A2 A T 1.55 0.098AllvsAll add 0 hDV70751704 rs16941401 LRRC37A2 T A 1.56 0.089 AllvsAlladd 0 hDV70751706 rs16941404 LRRC37A2 G C 1.39 0.068 AllvsAll add 0.453hDV70977122 rs17616652 LRRC37A2 A G 1.84 0.001 AllvsAll add 0.042 notes:*allele frequency, OR, and p-value are for the risk allele **validcounts for each SNP Study design in UCSF1: MI cases vs No CHD controls

TABLE 11 Risk factors for MI in participants of three case-controlstudies Study 1 Study 2 Study 3 Cases Controls Cases Controls CasesControls (n = 762) (n = 857) (n = 579) (n = 1159) (n = 475) (n = 619)Male, % 60 41 81 42 61 62 Age at enrollment, median (range) 62 (29-87)65 (24-100) 66 (28-88) 58 (45-97) 60 (32-86) 58 (37-88) Age at MI,median (range) 52 (27-82) NA 57 (21-70) NA  53 (29-77)^(†) NA Smoking, %66 45 68 40 73 54 Diabetes, % 20   0^(‡) 25   0^(‡) 38 10Dyslipidemia^(§), % 84 53 84 61 95 56 Hypertension^(||), % 61 32 66 3396 78 BMI (kg/m²), mean ± SD 28 ± 5 26 ± 5 28 ± 5 26 ± 5 31 ± 6 30 ± 7^(†)Data available for 254 cases. ^(‡)Individuals with diabetes wereexcluded from control group. ^(§)Dyslipidemia was defined in Study 1 andStudy 2 to be self-reported history of a physician diagnosis ofdyslipidemia or the use of lipid lowering prescription medication(s) anddefined in Study 3 to be the use of lipid lowering prescriptionmedication(s), LDL cholesterol >129 mg/dL, triglycerides >149 mg/dL orHDL cholesterol <45 mg/dL. ^(||)Hypertension was defined in Study 1 andStudy 2 to be a self-reported history of a physician diagnosis ofhypertension or use of antihypertensive prescription medication(s) anddefined in Study 3 to be the use of antihypertensive prescriptionmedication(s), systolic blood pressure >160 mmHg, or diastolic bloodpressure >90 mmHg. NA; not applicable.

TABLE 12 Twenty-four SNPs associated with MI in Study 1 and Study 2Study 1 Study 2 Risk Risk Risk Allele Allele P value SNP Gene SymbolAllele Freq. P value OR 95% CI Freq. (1-sided) OR 90% CI rs11568658ABCC4 G 0.97 0.005 1.98 1.24-3.16 0.97 0.01 1.81 1.19-2.77 rs16875009ADAMTS16 A 0.13 0.005 1.33 1.09-1.62 0.13 0.005 1.29 1.10-1.51 rs25651ANPEP T 0.29 0.0001 1.36 1.17-1.58 0.31 0.02 1.17 1.03-1.33 rs439401APOE T 0.35 0.03 1.17 1.01-1.35 0.37 0.01 1.19 1.05-1.35 rs867852C1orf81 T 0.78 0.03 1.22 1.02-1.45 0.78 0.04 1.17 1.01-1.37 rs28372907DHX33 A 0.18 0.03 1.21 1.02-1.44 0.18 0.01 1.22 1.05-1.42 rs11553576EML3 T 0.60 0.03 1.17 1.02-1.35 0.60 0.03 1.16 1.02-1.31 rs1325920 ENO1A 0.80 0.02 1.24 1.03-1.48 0.80 0.007 1.26 1.08-1.48 rs31208 FAM71B G0.11 0.03 1.27 1.03-1.57 0.12 0.006 1.30 1.09-1.55 rs3793456 FXN G 0.560.01 1.20 1.05-1.39 0.55 0.03 1.15 1.02-1.30 rs10890 FXN T 0.43 0.0041.23 1.07-1.42 0.43 0.03 1.15 1.02-1.30 rs35410698 HLA-DPB2 G 0.93 0.021.43 1.06-1.91 0.94 0.006 1.53 1.16-2.03 rs1136141 HSPA8 G 0.86 0.051.24 1.00-1.53 0.86 0.02 1.26 1.05-1.52 rs7928656 KCTD14 A 0.84 0.041.23 1.01-1.51 0.84 0.004 1.32 1.11-1.57 rs3740918 KIRREL3 G 0.69 0.0031.26 1.08-1.46 0.70 0.01 1.20 1.05-1.37 rs725660 LOC388553 A 0.34 0.0061.23 1.06-1.42 0.35 0.0009 1.26 1.12-1.43 rs3798220 LPA C 0.02 0.04 1.591.03-2.48 0.02 0.008 1.72 1.19-2.49 rs11711953 MAP4 T 0.07 0.03 1.341.03-1.73 0.07 0.01 1.35 1.09-1.67 rs4907956 OLFM3 G 0.60 0.03 1.181.02-1.36 0.61 0.01 1.19 1.05-1.34 rs2290819 PTPRM T 0.38 0.03 1.171.01-1.35 0.38 0.008 1.20 1.06-1.35 rs3204635 STAC3 A 0.25 0.02 1.201.03-1.40 0.26 0.03 1.16 1.02-1.33 rs1866389 THBS4 C 0.20 0.03 1.211.02-1.43 0.20 0.03 1.19 1.03-1.37 rs3812475 TRMT12 T 0.50 0.03 1.161.01-1.34 0.52 0.04 1.13 1.01-1.28 rs862708 ZNF304 C 0.02 0.003 1.881.24-2.83 0.03 0.03 1.45 1.05-2.00

TABLE 13 Genotypic association of five SNPs in Study 3 SNP CasesControls Age and Sex adjusted Fully Adjusted (gene symbol) Genotype n(%) n (%) OR 90% CI P value OR 90% CI P value rs1325920 AA 327 (71) 394(65) 1.61 0.92-2.81 0.08 1.28 0.62-2.62 0.3 (ENO1) GA 120 (26) 186 (31)1.25 0.70-2.22 0.3 1.20 0.57-2.54 0.3 GG 14 (3) 27 (4) ref ref Additive1.28 1.06-1.55 0.01 1.09 0.85-1.38 0.3 rs10890 TT 117 (25)  98 (16) 1.521.14-2.04 0.009 1.49 1.02-2.18 0.04 (FXN) CT 201 (44) 325 (54) 0.790.62-0.99 0.9 0.85 0.63-1.16 0.8 CC 143 (31) 183 (30) ref ref Additive1.18 1.02-1.37 0.03 1.18 0.98-1.42 0.07 rs3793456 GG 174 (38) 180 (30)1.33 0.98-1.80 0.06 1.50 1.01-2.22 0.04 (FXN) AG 205 (45) 319 (53) 0.880.66-1.18 0.8 1.00 0.69-1.45 0.5 AA  78 (17) 107 (18) ref ref Additive1.21 1.04-1.40 0.02 1.26 1.05-1.53 0.02 rs35410698 GG 426 (92) 539 (89)1.56 1.09-2.22 0.02 2.07 1.31-3.27 0.004 (HLA-DPB2) GA 36 (8)  70 (11)ref ref Additive 1.46 1.03-2.06 0.04 1.79 1.14-2.81 0.02 rs3798220 CT 41(9) 12 (2) 4.63 2.67-8.03 <0.001 3.52 1.85-6.69 0.001 (LPA) TT 416 (91)573 (98) ref ref Additive 4.63 2.67-8.03 <0.001 3.52 1.85-6.69 0.001

TABLE 14 Non- UCSF1(S0012) Risk Risk Case Control Al- Al- Case ControlAllele Allele Marker gene lele lele Samples** Samples** Freq* Freq* OR* OR95L* OR95U* P-value* stratum Model hCV16065831 ENO1 T C 735 854 0.550.51 1.15 1.00 1.33 0.051 All additive hCV25996298 SLC45A1 T G 734 8550.82 0.80 1.16 0.97 1.39 0.095 All additive hCV3086961 RERE C A 735 8560.81 0.78 1.27 1.07 1.52 0.007 All additive hCV3087016 RERE C A 736 8480.80 0.77 1.19 1.00 1.41 0.050 All additive hCV32055477 RERE G A 733 8450.81 0.77 1.31 1.10 1.56 0.002 All additive hCV32055625 T C 733 852 0.820.78 1.26 1.05 1.50 0.011 All additive hCV32055654 G A 737 853 0.31 0.271.19 1.02 1.39 0.024 All additive hCV8824394 RERE T G 736 853 0.82 0.791.21 1.01 1.44 0.037 All additive hCV8881160 RERE C T 732 852 0.92 0.891.38 1.08 1.77 0.009 All additive hCV11398434 RERE C T 736 854 0.81 0.771.28 1.07 1.52 0.006 All additive hCV11398437 RERE C T 726 836 0.82 0.791.28 1.07 1.54 0.007 All additive hCV1188747 RERE G C 737 854 0.58 0.531.21 1.05 1.39 0.007 All additive hCV29819064 RERE C T 737 854 0.81 0.781.24 1.04 1.48 0.015 All additive hCV2987229 RERE C T 735 853 0.55 0.521.15 1.00 1.32 0.054 All additive hCV2987250 RERE G C 737 854 0.81 0.771.24 1.04 1.47 0.015 All additive hCV30233466 RERE G A 736 856 0.56 0.521.17 1.02 1.35 0.026 All additive hCV30287627 RERE T A 735 854 0.60 0.561.16 1.01 1.33 0.039 All additive hCV30467730 RERE T C 732 855 0.80 0.761.25 1.05 1.49 0.011 All additive hCV3086932 RERE G T 675 785 0.77 0.721.27 1.07 1.52 0.007 All additive hCV3086950 RERE A G 737 856 0.80 0.761.26 1.06 1.50 0.008 All additive hCV3086983 RERE T C 734 851 0.19 0.171.22 1.02 1.46 0.034 All additive hCV32055474 RERE G C 736 852 0.81 0.771.28 1.07 1.52 0.006 All additive hCV32055581 RERE A G 736 854 0.29 0.261.16 0.99 1.35 0.065 All additive hCV32055596 RERE G A 735 854 0.82 0.791.26 1.05 1.51 0.012 All additive hCV8379452 T C 737 853 0.56 0.51 1.191.04 1.37 0.012 All additive hCV8824244 ENO1 T C 735 851 0.81 0.79 1.190.99 1.42 0.063 All additive hCV8824248 ENO1 A G 736 855 0.82 0.79 1.201.01 1.44 0.042 All additive UCSF2(S0061) Non- Case Risk Risk CaseControl Al- Control r2 with Al- Al- Sam- Sam- lele Allele P- stra-hCV8824241 Marker gene lele lele ples** ples** Freq* Freq* OR* OR95L*OR95U* value* tum Model (ENO1)*** hCV16065831 ENO1 T C 558 1152 0.560.52 1.18 1.02 1.36 0.0225 All additive 0.238 hCV25996298 SLC45A1 T G555 1152 0.82 0.79 1.24 1.03 1.48 0.0211 All additive 0.214 hCV3086961RERE C A 558 1154 0.82 0.77 1.34 1.12 1.60 0.0016 All additive 0.451hCV3087016 RERE C A 558 1145 0.81 0.77 1.26 1.06 1.51 0.0105 Alladditive 0.416 hCV32055477 RERE G A 555 1149 0.82 0.77 1.33 1.11 1.590.0019 All additive 0.442 hCV32055625 T C 557 1153 0.82 0.78 1.27 1.071.52 0.0077 All additive 0.596 hCV32055654 G A 557 1153 0.31 0.29 1.350.97 1.88 0.0739 All re- 0.059 cessive hCV8824394 RERE T G 557 1154 0.820.78 1.28 1.06 1.53 0.0084 All additive 0.342 hCV8881160 RERE C T 5581152 0.91 0.89 1.30 1.02 1.65 0.0324 All additive 0.327 hCV11398434 REREC T 0.458 hCV11398437 RERE C T 0.45 hCV1188747 RERE G C 0.171hCV29819064 RERE C T 0.442 hCV2987229 RERE C T 0.102 hCV2987250 RERE G C0.416 hCV30233466 RERE G A 0.162 hCV30287627 RERE T A 0.149 hCV30467730RERE T C 0.418 hCV3086932 RERE G T 0.38 hCV3086950 RERE A G 0.425hCV3086983 RERE T C 0.025 hCV32055474 RERE G C 0.451 hCV32055581 RERE AG 0.047 hCV32055596 RERE G A 0.548 hCV8379452 T C 0.157 hCV8824244 ENO1T C 0.885 hCV8824248 ENO1 A G 0.87 note: *allele frequency, OR, andp-value are for the risk allele **valid counts for each SNP ***based onUCSF1 Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

TABLE 15 Non UCSF1(S0012) Risk Risk Case Control Al- Al- Case ControlAllele Allele Marker gene lele lele Samples** Samples** Freq* Freq* OR*OR95L* OR95U* P-value* stratum Model hCV29033518 A T 737 854 0.09 0.071.28 0.99 1.64 0.0569 additive ALL_ALL hCV472000 TJP2 G A 734 853 0.100.07 1.33 1.03 1.70 0.0263 additive ALL_ALL hCV28008078 FXN C T 735 8550.58 0.54 1.18 1.02 1.35 0.0219 additive ALL_ALL hCV30586985 FXN A G 736855 0.60 0.55 1.23 1.06 1.41 0.0047 additive ALL_ALL hCV27970553 TJP2 TC 731 850 0.43 0.40 1.17 1.01 1.35 0.0344 additive ALL_ALL hCV7442005TJP2 G A 737 851 0.49 0.44 1.22 1.06 1.40 0.0065 additive ALL_ALLhCV1463112 C T 734 853 0.59 0.55 1.16 1.01 1.34 0.0333 additive ALL_ALLhCV15892430 FXN C T 731 849 0.56 0.51 1.23 1.07 1.42 0.0038 additiveALL_ALL hCV1463224 FXN T C 737 854 0.49 0.43 1.25 1.08 1.44 0.0022additive ALL_ALL hCV1463222 FXN C T 730 856 0.49 0.43 1.26 1.10 1.460.0011 additive ALL_ALL hCV11761245 TJP2 C T 735 855 0.48 0.43 1.21 1.051.39 0.0071 additive ALL_ALL hCV1463184 FXN T C 735 853 0.81 0.79 1.731.06 2.83 0.0289 dominant ALL_ALL hCV1844077 TJP2 G A 736 855 0.75 0.721.19 0.98 1.45 0.0863 recessive ALL_ALL UCSF2(S0061) Non Case Risk RiskCase Control Al- Control r2 with Al- Al- Sam- Sam- lele Allele P- stra-hCV1463226 Marker gene lele lele ples** ples** Freq* Freq* OR* OR95L*OR95U* value* tum Model (FXN)*** hCV29033518 A T 558 1152 0.10 0.08 1.230.96 1.58 0.0977 add ALL_ALL 0.042 hCV472000 TJP2 G A 557 1150 0.09 0.071.30 0.98 1.71 0.0653 dom ALL_ALL 0.057 hCV28008078 FXN C T 0.446hCV30586985 FXN A G 0.572 hCV27970553 TJP2 T C 0.237 hCV7442005 TJP2 G A0.325 hCV1463112 C T 0.411 hCV15892430 FXN C T 0.435 hCV1463224 FXN T C0.99 hCV1463222 FXN C T 0.989 hCV11761245 TJP2 C T 0.343 hCV1463184 FXNT C 0.196 hCV1844077 TJP2 G A 0 note: *allele frequency, OR, and p-valueare for the risk allele **valid counts for each SNP ***based on UCSF1Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

TABLE 16 UCSF1 Case Case Control Allele Control Allele r{circumflex over( )}2 with marker rs Gene RiskAllele NonRiskAllele Samples** Samples**Freq* Freq* OR* OR95L* OR95U* P_value Strata Model hCV32055477 (RERE)hCV1188731 rs4908514 RERE T C 730 793 0.82 0.79 1.26 1.05 1.51 0.0141AllvsAll add 0.689 hCV1188735 rs10864366 RERE C T 734 793 0.82 0.79 1.251.05 1.50 0.0148 AllvsAll add 0.705 hCV15967490 rs2292242 SLC45A1 T C728 795 0.59 0.56 1.17 1.01 1.35 0.0367 AllvsAll add 0.167 hCV27157435rs7513420 RERE C T 735 794 0.60 0.57 1.17 1.01 1.35 0.0351 AllvsAll add0.358 hCV27157439 rs10779704 RERE C A 729 783 0.60 0.57 1.17 1.01 1.350.0369 AllvsAll add 0.35 hCV27884601 rs4908776 RERE C T 734 793 0.820.79 1.25 1.05 1.51 0.0148 AllvsAll add 0.64 hCV27958354 rs4908762 RERET C 731 794 0.80 0.77 1.23 1.03 1.46 0.0207 AllvsAll add 0.896hCV28023091 rs4908773 RERE C T 736 792 0.83 0.79 1.31 1.09 1.57 0.0044AllvsAll add 0.714 hCV29368919 rs4908513 RERE C T 729 796 0.83 0.79 1.281.06 1.53 0.0087 AllvsAll add 0.691 hCV2966448 rs1064826 RERE A G 734790 0.28 0.25 1.15 0.98 1.35 0.0971 AllvsAll add 0.071 hCV29873524rs7533113 RERE T C 725 793 0.82 0.79 1.27 1.05 1.52 0.0117 AllvsAll add0.701 hCV29945430 rs7517436 RERE T G 734 789 0.82 0.78 1.28 1.07 1.530.0076 AllvsAll add 0.641 hCV3086948 rs10864361 RERE C T 734 794 0.590.56 1.15 1.00 1.33 0.0496 AllvsAll add 0.345 hCV3087000 rs1463055 REREA G 736 796 0.81 0.77 1.26 1.06 1.50 0.0096 AllvsAll add 0.897hCV3087003 rs6577500 RERE C G 734 793 0.80 0.77 1.23 1.03 1.46 0.0202AllvsAll add 0.907 hCV3087008 rs12136689 RERE C A 723 794 0.33 0.29 1.150.99 1.35 0.0673 AllvsAll add 0.106 hCV3087015 rs11121198 RERE G C 735792 0.81 0.77 1.25 1.05 1.49 0.0125 AllvsAll add 0.901 hCV32055527rs10864364 RERE A C 736 795 0.83 0.79 1.29 1.07 1.54 0.0067 AllvsAll add0.699 hCV32055595 rs6577524 RERE T C 734 792 0.83 0.79 1.26 1.05 1.510.0149 AllvsAll add 0.693 hCV529178 rs301811 RERE T C 732 789 0.81 0.771.23 1.04 1.47 0.0178 AllvsAll add 0.895 hCV597227 rs301809 RERE T C 736793 0.81 0.77 1.26 1.06 1.50 0.0096 AllvsAll add 0.897 hCV8823713rs1472228 RERE T C 736 791 0.82 0.79 1.23 1.02 1.47 0.0276 AllvsAll add0.698 hCV8824424 rs1058790 RERE A G 735 793 0.82 0.79 1.23 1.03 1.470.0230 AllvsAll add 0.444 hCV8824425 rs1058791 RERE A C 723 792 0.820.79 1.20 1.00 1.44 0.0441 AllvsAll add 0.435 hCV8824453 rs1466654SLC45A1 T G 732 790 0.57 0.53 1.19 1.03 1.37 0.0187 AllvsAll add 0.149hCV8881161 rs926951 RERE G A 734 789 0.80 0.77 1.24 1.04 1.47 0.0167AllvsAll add 0.889 hCV8881164 rs1150398 RERE T C 733 786 0.98 0.97 1.530.94 2.48 0.0848 AllvsAll add 0.088 notes: *allele frequency, OR, andp-value are for the risk allele **valid counts for each SNP Study designin UCSF1: MI cases vs No CHD controls

TABLE 17 UCSF1 Case Control Case Control Allele Allele marker rs GeneRiskAllele NonRiskAllele Samples** Samples** Freq* Freq* OR* OR95L*hCV28993059 rs4832179 A G 770 920 0.09 0.08 1.25 0.99 hCV2091649rs12714147 VAMP5 G A 771 921 0.17 0.15 1.17 0.97 hCV8696079 rs960066 T G723 864 0.21 0.19 1.16 0.97 hCV2091650 rs10206961 RNF181 T C 723 8620.42 0.39 1.14 0.99 hCV11504800 rs10176176 T A 721 861 0.48 0.44 1.171.02 hCV8696050 rs1254901 VAMP8 G A 770 920 0.70 0.66 1.22 1.06hCV11942442 rs1254898 GGCX C T 718 862 0.70 0.66 1.18 1.02 hCV2091669rs11688233 T A 723 865 0.92 0.90 1.39 1.08 hCV2091674 rs6733550 TMEM150G T 716 862 0.37 0.34 1.14 0.99 r{circumflex over ( )}2 with hCV2091644marker rs Gene RiskAllele NonRiskAllele OR95U* P value Strata Model(VAMP8) hCV28993059 rs4832179 A G 1.58 0.0653 All add 0.019 hCV2091649rs12714147 VAMP5 G A 1.41 0.0935 All add 0.277 hCV8696079 rs960066 T G1.37 0.0986 All add 0.219 hCV2091650 rs10206961 RNF181 T C 1.31 0.0706All add 0.648 hCV11504800 rs10176176 T A 1.35 0.0291 All add 0.784hCV8696050 rs1254901 VAMP8 G A 1.41 0.0072 All add 0.323 hCV11942442rs1254898 GGCX C T 1.38 0.0272 All add 0.307 hCV2091669 rs11688233 T A1.78 0.0102 All add 0.064 hCV2091674 rs6733550 TMEM150 G T 1.33 0.0755All add 0.364 notes: *allele frequency, OR, and p-value are for the riskallele **valid counts for each SNP Study design in UCSF1: MI cases vs NoCHD controls

TABLE 18 UCSF1 Case Control Case Control Allele Allele marker rs GeneRiskAllele NonRiskAllele Samples** Samples** Freq* Freq* OR* OR95L*hCV11846435 rs6929299 LPA T C 760 852 0.67 0.61 1.26 1.09 hCV207123rs7771801 LPA C G 757 855 0.68 0.63 1.24 1.07 hCV25927459 rs3798221 LPAG T 752 855 0.83 0.79 1.28 1.07 hCV27462774 rs3127583 A G 735 797 0.160.13 1.26 1.02 hCV282793 rs11751605 LPA C T 761 855 0.16 0.14 1.19 0.98hCV29322781 rs6921516 LPA G A 734 795 0.68 0.63 1.24 1.07 hCV29809835rs9457880 A C 735 796 0.05 0.04 1.37 0.96 hCV29952522 rs9457931 LPAL2 GA 733 797 0.08 0.06 1.52 1.15 hCV30574599 rs7770628 LPA C T 728 794 0.490.45 1.17 1.02 hCV3201490 rs1321195 LPA G A 735 795 0.87 0.85 1.26 1.02hCV334752 rs6939089 LPA T C 758 853 0.68 0.63 1.24 1.08 hDV70715669rs16891445 T A 735 795 0.05 0.04 1.46 1.02 hDV70973697 rs17593921SLC22A3 C T 735 796 0.98 0.97 1.62 1.01 hCV31161091 rs3127573 SLC22A2 GA 733 788 0.13 0.11 1.27 1.00 hCV1550877 rs6919346 LPA C T 759 851 0.850.83 1.24 1.00 hCV2335281 rs519118 SLC22A3 T G 733 796 0.54 0.52 1.291.03 hCV3111822 rs316025 SLC22A2 T C 735 794 0.28 0.26 1.42 0.95hCV561574 rs624319 SLC22A3 G A 733 796 0.55 0.52 1.29 1.03 r{circumflexover ( )}2 with hCV25930271 marker rs Gene RiskAllele NonRiskAlleleOR95U* P value Strata Model (LPA) hCV11846435 rs6929299 LPA T C 1.460.0018 All add 0.01 hCV207123 rs7771801 LPA C G 1.44 0.0038 All add0.009 hCV25927459 rs3798221 LPA G T 1.53 0.0058 All add 0.004hCV27462774 rs3127583 A G 1.54 0.0304 All add 0.004 hCV282793 rs11751605LPA C T 1.43 0.0780 All add 0.005 hCV29322781 rs6921516 LPA G A 1.450.0044 All add 0.008 hCV29809835 rs9457880 A C 1.96 0.0828 All add 0hCV29952522 rs9457931 LPAL2 G A 2.01 0.0030 All add 0.352 hCV30574599rs7770628 LPA C T 1.35 0.0281 All add 0.014 hCV3201490 rs1321195 LPA G A1.54 0.0292 All add 0.004 hCV334752 rs6939089 LPA T C 1.44 0.0032 Alladd 0.009 hDV70715669 rs16891445 T A 2.08 0.0378 All add 0 hDV70973697rs17593921 SLC22A3 C T 2.61 0.0475 All add 0 hCV31161091 rs3127573SLC22A2 G A 1.61 0.0541 All dom 0.004 hCV1550877 rs6919346 LPA C T 1.530.0519 All rec 0.004 hCV2335281 rs519118 SLC22A3 T G 1.61 0.0284 All rec0.021 hCV3111822 rs316025 SLC22A2 T C 2.12 0.0857 All rec 0.005hCV561574 rs624319 SLC22A3 G A 1.61 0.0276 All rec 0.021 notes: *allelefrequency, OR, and p-value are for the risk allele **valid counts foreach SNP Study design in UCSF1: MI cases vs No CHD controls

TABLE 19 Meta-analysis of UCSF1 and UCSF2 myocardial infarction (MI)risk Non- Case Control Risk Risk Case Control Allele Allele marker GeneChr Allele Allele Samples** Samples** Freq* Freq* OR* 95% CI* P value*Strata Model hCV11846435 LPA 6 T C 1329 1994 0.67 0.63 1.22 1.10-1.360.0001 AllvsAll add hCV1550877 LPA 6 C T 1327 2003 0.84 0.82 1.171.02-1.34 0.0203 AllvsAll add hCV207123 LPA 6 C G 1331 2010 0.68 0.651.17 1.05-1.30 0.0034 AllvsAll add hCV2335281 SLC22A3 6 T G 1306 19520.53 0.51 1.19 1.01-1.39 0.0324 AllvsAll rec hCV25927459 LPA 6 G T 13252008 0.82 0.80 1.16 1.02-1.32 0.0198 AllvsAll add hCV25930271 LPA 6 C T1338 2015 0.03 0.02 1.66 1.21-2.26 0.0015 AllvsAll add hCV27422538 LPA 6C G 1335 2015 0.80 0.77 1.25 1.10-1.41 0.0004 AllvsAll add hCV27462774 6A G 1308 1954 0.15 0.13 1.18 1.03-1.36 0.0214 AllvsAll add hCV282793 LPA6 C T 1334 2010 0.16 0.14 1.20 1.04-1.37 0.0106 AllvsAll add hCV29322781LPA 6 G A 1307 1949 0.68 0.65 1.16 1.04-1.29 0.0063 AllvsAll addhCV29952522 LPAL2 6 G A 1307 1952 0.08 0.06 1.36 1.12-1.65 0.0020AllvsAll add hCV30574599 LPA 6 C T 1298 1944 0.48 0.46 1.09 0.99-1.210.0824 AllvsAll add hCV3111822 SLC22A2 6 T C 1308 1949 0.28 0.26 1.121.00-1.25 0.0496 AllvsAll add hCV31161091 SLC22A2 6 G A 1307 1942 0.130.11 1.20 1.03-1.39 0.0202 AllvsAll add hCV3201490 LPA 6 G A 1308 19510.88 0.85 1.27 1.09-1.47 0.0016 AllvsAll add hCV334752 LPA 6 T C 13282006 0.68 0.64 1.17 1.06-1.30 0.0029 AllvsAll add hCV561574 SLC22A3 6 GA 1307 1951 0.54 0.52 1.10 0.99-1.21 0.0676 AllvsAll add hDV70973697SLC22A3 6 C T 1308 1951 0.98 0.97 1.31 0.96-1.78 0.0930 AllvsAll addNon- Risk Risk Lp(a) level marker Gene Chr Allele Allele Samples**Estimate* 95% CI* P value* Strata Model hCV11846435 LPA 6 T C 911 0.1220.06-0.19 1.95E−04 AllvsAll add hCV1550877 LPA 6 C T 914 0.190 0.11-0.272.73E−06 AllvsAll add hCV207123 LPA 6 C G 915 0.076 0.01-0.14 0.0213AllvsAll add hCV2335281 SLC22A3 6 T G 892 0.093 0.03-0.15 0.0028AllvsAll add hCV25927459 LPA 6 G T 911 0.214 0.14-0.29 4.53E−08 AllvsAlladd hCV25930271 LPA 6 C T 916 0.706 0.51-0.91 7.59E−12 AllvsAll addhCV27422538 LPA 6 C G 917 0.236 0.16-0.31 3.63E−10 AllvsAll addhCV27462774 6 A G 893 0.164 0.07-0.26 5.34E−04 AllvsAll add hCV282793LPA 6 C T 915 0.148 0.06-0.24 0.0012 AllvsAll add hCV29322781 LPA 6 G A892 0.076 0.01-0.14 0.0239 AllvsAll add hCV29952522 LPAL2 6 G A 8920.308 0.18-0.44 3.07E−08 AllvsAll add hCV30574599 LPA 6 C T 887 0.0890.03-0.15 0.0050 AllvsAll add hCV3111822 SLC22A2 6 T C 892 0.0700.00-0.14 0.0562 AllvsAll add hCV31161091 SLC22A2 6 G A 889 0.1260.03-0.22 0.0127 AllvsAll add hCV3201490 LPA 6 G A 893 0.233 0.14-0.324.54E−07 AllvsAll add hCV334752 LPA 6 T C 911 0.073 0.01-0.14 0.0274AllvsAll add hCV561574 SLC22A3 6 G A 891 0.099 0.04-0.16 0.0013 AllvsAlladd hDV70973697 SLC22A3 6 C T 891 0.210 0.04-0.38 0.0177 AllvsAll addnote: *Data for allele frequency, OR and P-value were provided for riskalleles in this table **Valid counts for each SNP Study design for MIendpoint: MI cases vs controls having no history of CHD in UCSF1 andUCSF2 Study design for Lp(a) level endpoint: all patients with availableLp(a) level in UCSF1 and UCSF2; Lp(a) level was transformed toLog10Lp(a)

TABLE 20 UCSF1(S0012) Non Case Control Risk Risk Case Control AlleleAllele Marker Gene chr Allele Allele Samples** Samples** Freq* Freq* OR*95% CI* P-value* stratum Model hCV22274679 TRMT12 8 C T 737 853 0.540.50 1.16 (1.01-1.34) 0.0344 All additive hCV11688401 OR2H1 6 G A 736854 0.27 0.24 1.15 (0.98-1.35) 0.0833 All additive hDV70661573 ADAMTS1 5T A 710 826 0.17 0.13 1.33 (1.09-1.62) 0.0048 All additive hCV11854426KCNB2 8 T C 737 856 0.13 0.11 1.21 (0.97-1.50) 0.0837 All additivehCV2531730 CHKB 22 A T 732 851 0.41 0.38 1.15 (1.00-1.33) 0.0532 Alladditive hCV3259235 EIF4E3 3 A G 732 848 0.12 0.10 1.23 (0.99-1.53)0.0640 All additive hCV904974 19 C T 729 852 0.39 0.35 1.17 (1.01-1.35)0.0325 All additive hDV68873046 C20orf23 20 A T 736 852 0.98 0.97 1.70(1.09-2.66) 0.0204 All additive UCSF2(S0061) Non Case Control Risk RiskCase Control Allele Allele P- Marker Gene chr Allele Allele Samples**Samples** Freq* Freq* OR* 95% CI* value* stratum Model hCV22274679TRMT12 8 C T 574 1157 0.55 0.52 1.13 (0.98-1.30) 0.0832 All additivehCV11688401 OR2H1 6 G A 558 1154 0.26 0.23 1.21 (0.98-1.48) 0.0705 Alldominant hDV70661573 ADAMTS1 5 T A 558 1153 0.17 0.13 1.29 (1.06-1.56)0.0102 All additive hCV11854426 KCNB2 8 T C 553 1138 0.14 0.12 1.22(0.97-1.55) 0.0918 All dominant hCV2531730 CHKB 22 A T 557 1154 0.410.38 1.15 (0.99-1.33) 0.0659 All additive hCV3259235 EIF4E3 3 A G 5571152 0.12 0.10 1.21 (0.96-1.52) 0.0996 All additive hCV904974 19 C T 5581151 0.41 0.37 1.19 (1.03-1.38) 0.0200 All additive hDV68873046 C20orf2320 A T 558 1154 0.98 0.97 1.52 (0.95-2.44) 0.0815 All additive notes:*allele frequency, OR, and p-value are for the risk allele **validcounts for each SNP Study design in UCSF1 and UCSF2: MI cases vs No CHDcontrols

TABLE 21 CHD Risk Reduction by Pravastatin in CARE According to SNPGenotypes EVENTS NONEVENT EVENTS NONEVENT Gene End- (Pravastatin(Pravastatin (placebo (placebo P Allele1 Allele2 SNP rs symbol pointStrata arm) arm) arm) arm) P value HR HR95L HR95U interaction Allele1Freq. Allele2 Freq. hCV16189421 rs1048755 ATXN3 endpt1 TC + TT 65 526 62496 0.9853 1 0.708 1.421 0.0830 T 0.24 C 0.76 hCV16189421 rs1048755ATXN3 endpt1 CC 68 729 97 684 0.0101 0.67 0.488 0.907 0.0830 T 0.24 C0.76 hCV25630686 PSMB9 endpt1 TC + TT 5 85 14 78 0.0453 0.35 0.127 0.9780.0993 T 0.03 C 0.97 hCV25630686 PSMB9 endpt1 CC 128 1206 151 11340.0728 0.81 0.637 1.02 0.0993 T 0.03 C 0.97 hCV25631989 rs1135983 ATF6endpt1 TC + TT 26 198 13 187 0.0761 1.83 0.939 3.555 0.0080 T 0.08 C0.92 hCV25631989 rs1135983 ATF6 endpt1 CC 107 1044 145 1001 0.0099 0.720.561 0.924 0.0080 T 0.08 C 0.92 hCV25644901 ITGA9 endpt1 GA + GG 9 12026 103 0.0029 0.32 0.148 0.674 0.0093 G 0.05 A 0.95 hCV25644901 ITGA9endpt1 AA 124 1171 139 1111 0.2050 0.86 0.671 1.089 0.0093 G 0.05 A 0.95hCV25651076 rs5743291 NOD2 endpt1 AG + AA 28 217 21 195 0.5467 1.190.676 2.096 0.0926 A 0.09 G 0.91 hCV25651076 rs5743291 NOD2 endpt1 GG104 1068 144 1021 0.0061 0.7 0.546 0.904 0.0926 A 0.09 G 0.91hCV25651174 rs9277356 HLA-DPB1 endpt1 GA + GG 76 641 79 625 0.7173 0.940.689 1.293 0.0684 G 0.30 A 0.70 hCV25651174 rs9277356 HLA-DPB1 endpt1AA 57 643 86 585 0.0046 0.62 0.441 0.861 0.0684 G 0.30 A 0.70hCV25767417 rs3803430 ALDH1A3 endpt1 GA + GG 3 52 14 67 0.0565 0.3 0.0851.034 0.0897 G 0.02 A 0.98 hCV25767417 rs3803430 ALDH1A3 endpt1 AA 1301239 151 1145 0.0703 0.81 0.637 1.018 0.0897 G 0.02 A 0.98 hCV25922320rs12360861 CD6 endpt1 AG + AA 62 439 56 466 0.4063 1.17 0.812 1.6730.0033 A 0.21 G 0.79 hCV25922320 rs12360861 CD6 endpt1 GG 70 850 109 7450.0003 0.58 0.428 0.781 0.0033 A 0.21 G 0.79 hCV25922440 rs34362748 GALCendpt1 TC + TT 30 377 50 341 0.0139 0.57 0.36 0.891 0.0728 T 0.16 C 0.84hCV25922440 rs34362748 GALC endpt1 CC 103 881 109 849 0.5029 0.91 0.6971.194 0.0728 T 0.16 C 0.84 hCV25922816 rs36013429 PPOX endpt1 AG + AA 14184 27 145 0.0118 0.44 0.229 0.832 0.0487 A 0.07 G 0.93 hCV25922816rs36013429 PPOX endpt1 GG 119 1075 134 1045 0.2573 0.87 0.677 1.110.0487 A 0.07 G 0.93 hCV25926178 rs12882130 MARK3 endpt1 GC + GG 80 786111 714 0.0060 0.67 0.502 0.891 0.0710 G 0.38 C 0.62 hCV25926178rs12882130 MARK3 endpt1 CC 52 478 50 477 0.8351 1.04 0.707 1.536 0.0710G 0.38 C 0.62 hCV25926771 rs4906321 MARK3 endpt1 CT + CC 79 778 114 7110.0035 0.65 0.49 0.869 0.0316 C 0.31 T 0.69 hCV25926771 rs4906321 MARK3endpt1 TT 53 482 47 478 0.6009 1.11 0.75 1.645 0.0316 C 0.31 T 0.69hCV25927605 HLA-DPA1 endpt1 TC + TT 10 80 3 74 0.1082 2.88 0.792 10.4660.0216 T 0.03 C 0.97 hCV25927605 HLA-DPA1 endpt1 CC 122 1206 162 11360.0067 0.72 0.571 0.914 0.0216 T 0.03 C 0.97 hCV25928135 ADAM12 endpt1CT + CC 41 479 63 430 0.0091 0.59 0.4 0.878 0.0741 C 0.21 T 0.79hCV25928135 ADAM12 endpt1 TT 92 785 97 756 0.5831 0.92 0.694 1.2280.0741 C 0.21 T 0.79 hCV25941408 rs28497577 MYLK endpt1 TG + TT 18 23838 208 0.0035 0.43 0.248 0.761 0.0191 T 0.10 G 0.90 hCV25941408rs28497577 MYLK endpt1 GG 115 1052 125 1010 0.3660 0.89 0.691 1.1460.0191 T 0.10 G 0.90 hCV25942539 rs2401751 PTPN21 endpt1 AG + AA 63 70098 682 0.0067 0.65 0.47 0.886 0.0496 A 0.34 G 0.66 hCV25942539 rs2401751PTPN21 endpt1 GG 70 559 62 511 0.8839 1.03 0.729 1.444 0.0496 A 0.34 G0.66 hCV26000635 rs7020782 PAPPA endpt1 CA + CC 82 665 84 645 0.80060.96 0.709 1.304 0.0322 C 0.31 A 0.69 hCV26000635 rs7020782 PAPPA endpt1AA 51 624 81 566 0.0024 0.58 0.409 0.824 0.0322 C 0.31 A 0.69 hCV2633049rs2302006 CCL24 endpt1 GT + GG 48 440 47 443 0.8749 1.03 0.691 1.5440.0812 G 0.20 T 0.81 hCV2633049 rs2302006 CCL24 endpt1 TT 85 849 117 7710.0050 0.67 0.507 0.887 0.0812 G 0.20 T 0.81 hCV2658421 rs3176975 APOHendpt1 AC + AA 48 522 80 494 0.0037 0.59 0.412 0.842 0.0496 A 0.23 C0.77 hCV2658421 rs3176975 APOH endpt1 CC 84 769 84 718 0.6671 0.94 0.6921.266 0.0496 A 0.23 C 0.77 hCV2741051 rs2230806 ABCA1 endpt1 TC + TT 66645 62 593 0.9717 0.99 0.703 1.406 0.0576 T 0.28 C 0.72 hCV2741051rs2230806 ABCA1 endpt1 CC 67 647 103 624 0.0038 0.63 0.467 0.864 0.0576T 0.28 C 0.72 hCV2741083 rs4149313 ABCA1 endpt1 CT + CC 36 316 23 2890.2143 1.39 0.826 2.351 0.0119 C 0.13 T 0.87 hCV2741083 rs4149313 ABCA1endpt1 TT 97 976 142 927 0.0020 0.67 0.515 0.862 0.0119 C 0.13 T 0.87hCV2932115 rs5517 KLK1 endpt1 CT + CC 75 591 77 566 0.7201 0.94 0.6871.297 0.0755 C 0.27 T 0.73 hCV2932115 rs5517 KLK1 endpt1 TT 58 701 88651 0.0050 0.62 0.447 0.867 0.0755 C 0.27 T 0.73 hCV2983035 rs9527026 KLendpt1 AG + AA 36 387 53 321 0.0110 0.58 0.378 0.882 0.0944 A 0.15 G0.85 hCV2983035 rs9527026 KL endpt1 GG 97 903 110 893 0.3656 0.88 0.6711.158 0.0944 A 0.15 G 0.85 hCV3026189 rs11739136 KCNIP1 endpt1 TC + TT29 241 23 234 0.4448 1.24 0.716 2.14 0.0557 T 0.10 C 0.90 hCV3026189rs11739136 KCNIP1 endpt1 CC 104 1050 142 984 0.0048 0.69 0.54 0.8950.0557 T 0.10 C 0.90 hCV3068176 rs1801394 MTRR endpt1 AG + AA 100 908110 873 0.3839 0.89 0.676 1.162 0.0609 A 0.46 G 0.54 hCV3068176rs1801394 MTRR endpt1 GG 33 384 55 345 0.0062 0.55 0.355 0.842 0.0609 A0.46 G 0.54 hCV3111721 rs33950747 NPHS1 endpt1 TC + TT 11 191 19 1260.0160 0.4 0.191 0.844 0.0645 T 0.06 C 0.94 hCV3111721 rs33950747 NPHS1endpt1 CC 121 1098 146 1088 0.1265 0.83 0.651 1.055 0.0645 T 0.06 C 0.94hCV529706 rs428785 ADAMTS1 endpt1 CG + CC 55 569 80 476 0.0036 0.6 0.4260.846 0.0611 C 0.24 G 0.76 hCV529706 rs428785 ADAMTS1 endpt1 GG 77 71984 735 0.6603 0.93 0.685 1.271 0.0611 C 0.24 G 0.76 hCV529710 rs402007ADAMTS1 endpt1 CG + CC 57 570 81 480 0.0052 0.62 0.44 0.866 0.0858 C0.24 G 0.76 hCV529710 rs402007 ADAMTS1 endpt1 GG 76 720 84 737 0.61550.92 0.677 1.26 0.0858 C 0.24 G 0.76 hCV5478 rs1800574 TCF1 endpt1 TC +TT 11 75 4 76 0.0953 2.65 0.843 8.319 0.0175 T 0.03 C 0.97 hCV5478rs1800574 TCF1 endpt1 CC 122 1217 161 1141 0.0067 0.72 0.571 0.9140.0175 T 0.03 C 0.97 hCV549926 rs1057141 Tap1or endpt1 CT + CC 33 395 58354 0.0042 0.54 0.35 0.822 0.0495 C 0.16 T 0.84 hCV549926 rs1057141Tap1or endpt1 TT 99 894 107 857 0.3934 0.89 0.675 1.167 0.0495 C 0.16 T0.84 hCV594695 rs45551939 SERPINA1 endpt1 AT + AA 19 115 11 92 0.35481.42 0.675 2.997 0.0813 A 0.04 T 0.96 hCV594695 rs45551939 SERPINA1endpt1 TT 112 1169 154 1121 0.0055 0.71 0.555 0.904 0.0813 A 0.04 T 0.96hCV598677 rs5370 EDN1 endpt1 TG + TT 44 518 70 459 0.0035 0.57 0.3910.831 0.0339 T 0.22 G 0.78 hCV598677 rs5370 EDN1 endpt1 GG 89 774 93 7590.7179 0.95 0.709 1.268 0.0339 T 0.22 G 0.78 hCV7441704 rs1800205 PPT1endpt1 GA + GG 7 118 18 109 0.0354 0.39 0.164 0.938 0.0966 G 0.05 A 0.95hCV7441704 rs1800205 PPT1 endpt1 AA 125 1169 147 1107 0.0868 0.81 0.641.031 0.0966 G 0.05 A 0.95 hCV7443062 rs897453 PEMT endpt1 TC + TT 102897 107 865 0.5540 0.92 0.702 1.208 0.0186 T 0.45 C 0.55 hCV7443062rs897453 PEMT endpt1 CC 31 395 57 350 0.0021 0.5 0.325 0.78 0.0186 T0.45 C 0.55 hCV7475492 rs1138469 HSPG2 endpt1 TC + TT 23 156 22 1850.5131 1.22 0.677 2.181 0.0988 T 0.07 C 0.93 hCV7475492 rs1138469 HSPG2endpt1 CC 109 1132 142 1026 0.0072 0.71 0.553 0.912 0.0988 T 0.07 C 0.93hCV7490135 rs1805082 NPC1 endpt1 CT + CC 85 924 126 866 0.0018 0.64 0.490.849 0.0207 C 0.47 T 0.53 hCV7490135 rs1805082 NPC1 endpt1 TT 48 363 39345 0.4748 1.17 0.765 1.78 0.0207 C 0.47 T 0.53 hCV7494810 rs1058587GDF15 endpt1 GC + GG 46 559 80 517 0.0017 0.56 0.389 0.804 0.0241 G 0.25C 0.75 hCV7494810 rs1058587 GDF15 endpt1 CC 86 730 85 697 0.7657 0.960.708 1.289 0.0241 G 0.25 C 0.75 hCV7499212 rs1800127 LRP1 endpt1 TC +TT 5 63 14 56 0.0366 0.34 0.121 0.934 0.0831 T 0.02 C 0.98 hCV7499212rs1800127 LRP1 endpt1 CC 128 1229 151 1158 0.0771 0.81 0.639 1.0230.0831 T 0.02 C 0.98 hCV7514879 rs1800629 endpt1 AG + AA 33 403 55 3610.0048 0.54 0.348 0.827 0.0538 A 0.17 G 0.83 hCV7514879 rs1800629 endpt1GG 100 885 110 855 0.4029 0.89 0.679 1.168 0.0538 A 0.17 G 0.83hCV7577801 rs11876 SLC9A3R2 endpt1 TC + TT 56 491 48 468 0.6023 1.110.753 1.629 0.0200 T 0.22 C 0.78 hCV7577801 rs11876 SLC9A3R2 endpt1 CC77 798 117 741 0.0015 0.63 0.471 0.837 0.0200 T 0.22 C 0.78 hCV7618856rs1143675 ITGA4 endpt1 CT + CC 4 19 1 33 0.0972 6.39 0.714 57.205 0.0287C 0.01 T 0.99 hCV7618856 rs1143675 ITGA4 endpt1 TT 127 1264 163 11820.0114 0.74 0.588 0.935 0.0287 C 0.01 T 0.99 hCV783138 rs6046 F10 endpt1AG + AA 31 258 24 242 0.4753 1.21 0.713 2.069 0.0600 A 0.11 G 0.89hCV783138 rs6046 F10 endpt1 GG 101 1033 139 972 0.0051 0.69 0.537 0.8960.0600 A 0.11 G 0.89 hCV783184 rs510335 endpt1 TG + TT 32 282 27 2730.5952 1.15 0.688 1.918 0.0802 T 0.12 G 0.88 hCV783184 rs510335 endpt1GG 100 1008 137 942 0.0053 0.69 0.536 0.897 0.0802 T 0.12 G 0.88hCV7841642 rs11666735 FCAR endpt1 AG + AA 13 183 30 169 0.0103 0.430.222 0.817 0.0473 A 0.07 G 0.93 hCV7841642 rs11666735 FCAR endpt1 GG120 1108 135 1048 0.1808 0.85 0.661 1.081 0.0473 A 0.07 G 0.93hCV7900503 rs3732379 CX3CR1 endpt1 TC + TT 65 614 68 616 0.7875 0.950.679 1.341 0.0908 T 0.28 C 0.72 hCV7900503 rs3732379 CX3CR1 endpt1 CC68 677 97 600 0.0051 0.64 0.471 0.875 0.0908 T 0.28 C 0.72 hCV795441rs401502 IL12RB1 endpt1 GC + GG 81 690 79 649 0.8725 0.97 0.715 1.3290.0296 G 0.32 C 0.68 hCV795441 rs401502 IL12RB1 endpt1 CC 52 596 86 5650.0022 0.58 0.414 0.825 0.0296 G 0.32 C 0.68 hCV795442 rs375947 IL12RB1endpt1 GA + GG 80 691 77 651 0.9472 0.99 0.724 1.353 0.0218 G 0.32 A0.68 hCV795442 rs375947 IL12RB1 endpt1 AA 52 599 87 566 0.0016 0.580.408 0.812 0.0218 G 0.32 A 0.68 hCV8705506 rs5516 KLK1 endpt1 CG + CC66 749 96 667 0.0032 0.62 0.456 0.854 0.0480 C 0.34 G 0.66 hCV8705506rs5516 KLK1 endpt1 GG 67 543 69 550 0.9467 0.99 0.706 1.384 0.0480 C0.34 G 0.66 hCV8708474 rs1800468 MGC4093 endpt1 TC + TT 30 212 23 1940.5341 1.19 0.69 2.046 0.0851 T 0.09 C 0.91 hCV8708474 rs1800468 MGC4093endpt1 CC 103 1068 142 1013 0.0062 0.7 0.545 0.905 0.0851 T 0.09 C 0.91hCV8718197 rs1050998 CXCL16 endpt1 GA + GG 98 879 100 842 0.6535 0.940.71 1.24 0.0102 G 0.44 A 0.56 hCV8718197 rs1050998 CXCL16 endpt1 AA 33409 65 376 0.0008 0.49 0.322 0.744 0.0102 G 0.44 A 0.56 hCV8726337rs5498 ICAM1 endpt1 GA + GG 102 857 111 851 0.5198 0.92 0.7 1.198 0.0274G 0.44 A 0.56 hCV8726337 rs5498 ICAM1 endpt1 AA 31 430 53 365 0.00310.51 0.329 0.798 0.0274 G 0.44 A 0.56 hCV8848630 rs7192 HLA-DRA endpt1TG + TT 74 802 106 737 0.0054 0.66 0.487 0.883 0.0756 T 0.38 G 0.62hCV8848630 rs7192 HLA-DRA endpt1 GG 59 485 58 477 0.9870 1 0.698 1.4410.0756 T 0.38 G 0.62 hCV8851085 rs1042153 HLA-DPB1 endpt1 AG + AA 58 49158 484 0.9498 0.99 0.687 1.422 0.0838 A 0.22 G 0.78 hCV8851085 rs1042153HLA-DPB1 endpt1 GG 74 798 106 731 0.0049 0.65 0.485 0.878 0.0838 A 0.22G 0.78 hCV8895373 rs1503185 PTPRJ endpt1 AG + AA 53 409 44 394 0.53231.14 0.762 1.694 0.0203 A 0.18 G 0.82 hCV8895373 rs1503185 PTPRJ endpt1GG 80 882 120 820 0.0018 0.64 0.481 0.847 0.0203 A 0.18 G 0.82hCV8901525 rs861539 KLC1 endpt1 AG + AA 88 759 86 734 0.9319 0.99 0.7331.329 0.0204 A 0.37 G 0.63 hCV8901525 rs861539 KLC1 endpt1 GG 45 504 75457 0.0025 0.57 0.39 0.818 0.0204 A 0.37 G 0.63 hCV8921288 rs1060621GAPDH endpt1 CA + CC 36 440 73 403 0.0003 0.48 0.319 0.71 0.0008 C 0.20A 0.80 hCV8921288 rs1060621 GAPDH endpt1 AA 97 815 85 786 0.5588 1.090.815 1.459 0.0008 C 0.20 A 0.80 hCV904973 rs7412 APOE endpt1 TC + TT 19141 11 135 0.2198 1.59 0.757 3.348 0.0416 T 0.06 C 0.94 hCV904973 rs7412APOE endpt1 CC 114 1149 154 1081 0.0059 0.71 0.559 0.907 0.0416 T 0.06 C0.94 hCV9077561 rs1801274 FCGR2A endpt1 GA + GG 96 985 133 891 0.00270.67 0.515 0.87 0.0357 G 0.50 A 0.50 hCV9077561 rs1801274 FCGR2A endpt1AA 36 300 32 325 0.4605 1.2 0.743 1.926 0.0357 G 0.50 A 0.50 hCV9494470endpt1 TG + TT 33 407 54 365 0.0102 0.57 0.368 0.874 0.0957 T 0.17 G0.83 hCV9494470 endpt1 GG 100 884 111 851 0.3255 0.87 0.666 1.144 0.0957T 0.17 G 0.83 hCV9506149 rs1250259 FN1 endpt1 TA + TT 69 611 68 5820.8631 0.97 0.695 1.357 0.0654 T 0.28 A 0.72 hCV9506149 rs1250259 FN1endpt1 AA 64 678 97 634 0.0042 0.63 0.46 0.865 0.0654 T 0.28 A 0.72hCV9604851 rs1805002 CCKBR endpt1 AG + AA 19 113 14 140 0.1884 1.590.797 3.171 0.0273 A 0.05 G 0.95 hCV9604851 rs1805002 CCKBR endpt1 GG114 1178 151 1075 0.0046 0.7 0.552 0.898 0.0273 A 0.05 G 0.95 hCV2553030rs11230562 CD6 endpt1 TC + CC 129 1179 154 1151 0.1178 0.83 0.657 1.0480.0059 T 0.25 C 0.75 hCV2553030 rs11230562 CD6 endpt1 TT 3 107 11 630.0062 0.17 0.047 0.603 0.0059 T 0.25 C 0.75 hCV25637309 rs3204849 CCRL2endpt1 AT + TT 109 1107 150 994 0.0013 0.67 0.522 0.855 0.0031 A 0.39 T0.61 hCV25637309 rs3204849 CCRL2 endpt1 AA 24 184 15 219 0.0572 1.870.981 3.566 0.0031 A 0.39 T 0.61 hCV25640504 endpt1 TC + CC 113 1035 128977 0.1795 0.84 0.653 1.083 0.0390 T 0.28 C 0.72 hCV25640504 endpt1 TT12 194 28 175 0.0084 0.4 0.205 0.792 0.0390 T 0.28 C 0.72 hCV2769554rs1805010 IL4R endpt1 GA + AA 101 1001 144 939 0.0021 0.67 0.52 0.8650.0118 G 0.46 A 0.54 hCV2769554 rs1805010 IL4R endpt1 GG 32 287 21 2740.1841 1.45 0.837 2.518 0.0118 G 0.46 A 0.54 hCV2822674 rs1801222 CUBNendpt1 AG + GG 123 1140 144 1097 0.1375 0.83 0.655 1.06 0.0448 A 0.32 G0.68 hCV2822674 rs1801222 CUBN endpt1 AA 10 150 21 117 0.0120 0.38 0.1790.808 0.0448 A 0.32 G 0.68 hCV2992252 rs6037651 SIGLEC1 endpt1 CT + TT124 1089 140 1019 0.1532 0.84 0.658 1.068 0.0173 C 0.40 T 0.60hCV2992252 rs6037651 SIGLEC1 endpt1 CC 8 196 25 193 0.0052 0.32 0.1450.713 0.0173 C 0.40 T 0.60 hCV3187716 rs5186 AGTR1 endpt1 CA + AA 1281176 143 1093 0.1486 0.84 0.661 1.065 0.0111 C 0.30 A 0.70 hCV3187716rs5186 AGTR1 endpt1 CC 5 112 22 118 0.0061 0.26 0.097 0.679 0.0111 C0.30 A 0.70 hCV3215409 rs267561 ITGA9 endpt1 GA + AA 118 1057 128 9940.2979 0.88 0.682 1.124 0.0133 G 0.42 A 0.58 hCV3215409 rs267561 ITGA9endpt1 GG 15 235 37 222 0.0026 0.4 0.218 0.723 0.0133 G 0.42 A 0.58hCV3219460 rs1799983 NOS3 endpt1 TG + GG 124 1114 144 1065 0.1316 0.830.654 1.057 0.0495 T 0.35 G 0.65 hCV3219460 rs1799983 NOS3 endpt1 TT 9177 21 149 0.0157 0.38 0.175 0.834 0.0495 T 0.35 G 0.65 hCV370782rs9841174 SERPINI2 endpt1 CT + TT 113 1097 150 1022 0.0065 0.71 0.5580.91 0.0938 C 0.38 T 0.62 hCV370782 rs9841174 SERPINI2 endpt1 CC 20 19415 189 0.4473 1.3 0.664 2.532 0.0938 C 0.38 T 0.62 hCV7514870 rs1041981LTA endpt1 AC + CC 121 1118 144 1094 0.1397 0.83 0.655 1.061 0.0624 A0.33 C 0.67 hCV7514870 rs1041981 LTA endpt1 AA 12 172 21 122 0.0110 0.40.194 0.809 0.0624 A 0.33 C 0.67 hCV818008 rs5918 ITGB3 endpt1 CT + TT126 1266 164 1194 0.0099 0.74 0.584 0.929 0.0236 C 0.15 T 0.85 hCV818008rs5918 ITGB3 endpt1 CC 7 26 1 22 0.1271 5.11 0.628 41.557 0.0236 C 0.15T 0.85 hCV8708473 rs1800469 TMEM91 endpt1 AG + GG 124 1153 145 10900.1014 0.82 0.644 1.04 0.0991 A 0.32 G 0.68 hCV8708473 rs1800469 TMEM91endpt1 AA 9 139 20 125 0.0331 0.43 0.193 0.934 0.0991 A 0.32 G 0.68hCV8709053 rs4880 SOD2 endpt1 GA + AA 105 954 117 928 0.3282 0.88 0.6741.141 0.0636 G 0.50 A 0.50 hCV8709053 rs4880 SOD2 endpt1 GG 28 335 47285 0.0077 0.53 0.331 0.845 0.0636 G 0.50 A 0.50 hCV8737990 rs419598IL1RN endpt1 CT + TT 117 1193 157 1104 0.0035 0.7 0.551 0.89 0.0157 C0.28 T 0.72 hCV8737990 rs419598 IL1RN endpt1 CC 15 96 8 103 0.1156 1.990.844 4.699 0.0157 C 0.28 T 0.72 hCV8784787 rs688976 endpt1 AC + CC 1261234 163 1147 0.0088 0.73 0.581 0.925 0.0443 A 0.23 C 0.77 hCV8784787rs688976 endpt1 AA 6 57 2 69 0.1452 3.29 0.663 16.304 0.0443 A 0.23 C0.77 hCV8804621 rs1390938 SLC18A1 endpt1 AG + GG 125 1218 160 11320.0120 0.74 0.586 0.936 0.0805 A 0.25 G 0.75 hCV8804621 rs1390938SLC18A1 endpt1 AA 8 69 4 80 0.2298 2.09 0.628 6.934 0.0805 A 0.25 G 0.75hCV8851047 rs45614833 HLA-DPA1 endpt1 CT + TT 126 1229 158 1152 0.02240.76 0.602 0.962 0.0104 C 0.17 T 0.83 hCV8851047 rs45614833 HLA-DPA1endpt1 CC 7 32 1 37 0.0779 6.59 0.81 53.622 0.0104 C 0.17 T 0.83hCV8851065 rs9277343 HLA-DPA1 endpt1 GC + CC 120 1198 158 1120 0.00720.72 0.57 0.916 0.0322 G 0.28 C 0.72 hCV8851065 rs9277343 HLA-DPA1endpt1 GG 13 90 7 98 0.1152 2.1 0.835 5.264 0.0322 G 0.28 C 0.72hCV8851095 rs1042335 HLA-DPB1 endpt1 TC + CC 126 1216 157 1139 0.02290.76 0.603 0.963 0.0840 T 0.27 C 0.73 hCV8851095 rs1042335 HLA-DPB1endpt1 TT 7 40 4 50 0.1712 2.37 0.688 8.198 0.0840 T 0.27 C 0.73hCV9055799 rs3734311 IMPG1 endpt1 CG + GG 117 1040 142 1049 0.1628 0.840.658 1.073 0.0749 C 0.40 G 0.60 hCV9055799 rs3734311 IMPG1 endpt1 CC 15247 23 166 0.0153 0.45 0.233 0.857 0.0749 C 0.40 G 0.60 hCV9596963rs6115 SERPINA5 endpt1 GA + AA 106 1147 151 1098 0.0027 0.68 0.534 0.8770.0181 G 0.32 A 0.68 hCV9596963 rs6115 SERPINA5 endpt1 GG 26 136 14 1170.1985 1.53 0.8 2.934 0.0181 G 0.32 A 0.68 hCV997884 rs512770 endpt1AG + GG 126 1241 162 1143 0.0079 0.73 0.578 0.921 0.0466 A 0.20 G 0.80hCV997884 rs512770 endpt1 AA 5 42 2 63 0.1428 3.41 0.661 17.577 0.0466 A0.20 G 0.80 hCV2983036 rs9527025 KL endpt1 CC 4 22 2 27 0.3494 2.250.412 12.278 0.0793 C 0.15 G 0.85 hCV2983036 rs9527025 KL endpt1 CG 32363 51 293 0.0043 0.53 0.338 0.818 0.0793 C 0.15 G 0.85 hCV2983036rs9527025 KL endpt1 GG 97 906 112 891 0.2806 0.86 0.656 1.13 0.0793 C0.15 G 0.85 hCV3135085 rs10795446 CUBN endpt1 GG 10 147 21 145 0.06900.5 0.234 1.056 0.0932 G 0.33 T 0.67 hCV3135085 rs10795446 CUBN endpt1GT 64 554 61 532 0.9477 1.01 0.712 1.437 0.0932 G 0.33 T 0.67 hCV3135085rs10795446 CUBN endpt1 TT 57 575 82 529 0.0116 0.65 0.462 0.908 0.0932 G0.33 T 0.67 hCV3275199 rs2069885 IL9 endpt1 AA 5 28 2 21 0.5551 1.640.318 8.446 0.0775 A 0.13 G 0.87 hCV3275199 rs2069885 IL9 endpt1 AG 18310 35 257 0.0060 0.45 0.255 0.796 0.0775 A 0.13 G 0.87 hCV3275199rs2069885 IL9 endpt1 GG 109 947 128 937 0.2088 0.85 0.658 1.096 0.0775 A0.13 G 0.87 hCV342590 rs6030 F5 endpt1 CC 15 123 13 130 0.6256 1.2 0.5722.529 0.0995 C 0.31 T 0.69 hCV342590 rs6030 F5 endpt1 CT 44 553 74 5190.0034 0.57 0.394 0.832 0.0995 C 0.31 T 0.69 hCV342590 rs6030 F5 endpt1TT 74 613 78 566 0.4490 0.88 0.643 1.216 0.0995 C 0.31 T 0.69 hCV435368rs2812 PECAM1 endpt1 TT 40 272 44 270 0.6056 0.89 0.582 1.371 0.0948 T0.47 C 0.53 hCV435368 rs2812 PECAM1 endpt1 TC 56 649 86 573 0.0028 0.60.428 0.838 0.0948 T 0.47 C 0.53 hCV435368 rs2812 PECAM1 endpt1 CC 37369 34 373 0.7363 1.08 0.68 1.726 0.0948 T 0.47 C 0.53 hCV11170747rs2066853 AHR endpt1 GG 112 1008 128 982 0.2728 0.87 0.673 1.118 0.0356A 0.11 G 0.89 hCV11170747 rs2066853 AHR endpt1 AG + AA 20 283 36 2350.0036 0.44 0.256 0.767 0.0356 A 0.11 G 0.89 hCV11181829 rs5713 ACSM3endpt1 TT 124 1259 161 1189 0.0112 0.74 0.584 0.933 0.0735 C 0.01 T 0.99hCV11181829 rs5713 ACSM3 endpt1 CT + CC 8 23 4 26 0.2129 2.14 0.6467.125 0.0735 C 0.01 T 0.99 hCV11225994 rs1853021 LPA endpt1 GG 92 973130 894 0.0026 0.66 0.508 0.866 0.0671 A 0.13 G 0.87 hCV11225994rs1853021 LPA endpt1 AG + AA 37 311 34 314 0.7086 1.09 0.686 1.7410.0671 A 0.13 G 0.87 hCV11438723 rs1877273 WWOX endpt1 TT 0 12 3 130.9973 0 0 . 0.0772 T 0.10 C 0.90 hCV11438723 rs1877273 WWOX endpt1 TC +CC 133 1270 162 1194 0.0368 0.78 0.623 0.985 0.0772 T 0.10 C 0.90hCV11461296 JAK3 endpt1 GG 125 1204 155 1153 0.0389 0.78 0.616 0.9870.0111 C 0.02 G 0.98 hCV11461296 JAK3 endpt1 CG + CC 1 49 9 36 0.02550.09 0.012 0.749 0.0111 C 0.02 G 0.98 hCV11628130 rs2665802 GH1 endpt1TT 18 254 33 212 0.0116 0.48 0.269 0.848 0.0640 T 0.42 A 0.58hCV11628130 rs2665802 GH1 endpt1 TA + AA 113 1034 130 1001 0.2005 0.850.659 1.091 0.0640 T 0.42 A 0.58 hCV11642651 rs1800440 C2orf58 endpt1 CC3 54 10 43 0.0467 0.27 0.074 0.981 0.0718 C 0.19 T 0.81 hCV11642651rs1800440 C2orf58 endpt1 CT + TT 130 1237 155 1171 0.0651 0.8 0.6361.014 0.0718 C 0.19 T 0.81 hCV11689916 endpt1 AA 35 369 56 340 0.01590.59 0.39 0.907 0.0899 A 0.48 T 0.52 hCV11689916 endpt1 AT + TT 97 863102 816 0.5024 0.91 0.689 1.201 0.0899 A 0.48 T 0.52 hCV11697322rs1926447 CPB2 endpt1 GG 59 655 93 616 0.0037 0.62 0.445 0.854 0.0540 A0.29 G 0.71 hCV11697322 rs1926447 CPB2 endpt1 AG + AA 74 632 72 6000.8558 0.97 0.702 1.342 0.0540 A 0.29 G 0.71 hCV11764545 rs4961 ADD1endpt1 TT 2 52 7 41 0.0708 0.23 0.049 1.131 0.0921 T 0.18 G 0.82hCV11764545 rs4961 ADD1 endpt1 TG + GG 131 1238 158 1176 0.0573 0.80.634 1.007 0.0921 T 0.18 G 0.82 hCV11955747 rs9901673 CD68 endpt1 CC103 891 115 874 0.3731 0.89 0.679 1.156 0.0491 A 0.16 C 0.84 hCV11955747rs9901673 CD68 endpt1 AC + AA 30 399 50 341 0.0058 0.53 0.336 0.8320.0491 A 0.16 C 0.84 hCV11972326 rs5988 F13A1 endpt1 GG 13 69 8 800.2560 1.67 0.69 4.03 0.0738 G 0.24 C 0.76 hCV11972326 rs5988 F13A1endpt1 GC + CC 120 1217 156 1133 0.0103 0.73 0.577 0.929 0.0738 G 0.24 C0.76 hCV12020339 rs4531 DBH endpt1 GG 104 1095 145 1035 0.0043 0.690.538 0.891 0.0686 T 0.08 G 0.92 hCV12020339 rs4531 DBH endpt1 TG + TT28 192 20 174 0.4707 1.24 0.696 2.193 0.0686 T 0.08 G 0.92 hCV12108469CYP4A11 endpt1 AA 2 60 10 56 0.0353 0.2 0.043 0.893 0.0439 A 0.21 G 0.79hCV12108469 CYP4A11 endpt1 AG + GG 128 1225 155 1148 0.0427 0.79 0.6210.992 0.0439 A 0.21 G 0.79 hCV1243283 rs1716 ITGAE endpt1 AA 10 151 23113 0.0037 0.33 0.158 0.7 0.0173 A 0.33 G 0.67 hCV1243283 rs1716 ITGAEendpt1 AG + GG 123 1138 142 1101 0.1788 0.85 0.666 1.079 0.0173 A 0.33 G0.67 hCV1253630 rs2071307 ELN endpt1 GG 40 450 66 396 0.0030 0.55 0.3730.818 0.0332 A 0.41 G 0.59 hCV1253630 rs2071307 ELN endpt1 AG + AA 92839 96 813 0.6277 0.93 0.7 1.24 0.0332 A 0.41 G 0.59 hCV1345898rs2230804 CHUK endpt1 CC 21 322 38 281 0.0134 0.51 0.299 0.869 0.0835 C0.48 T 0.52 hCV1345898 rs2230804 CHUK endpt1 CT + TT 111 964 127 9300.2025 0.85 0.657 1.093 0.0835 C 0.48 T 0.52 hCV1361979 rs25683 ACAT2endpt1 GG 36 434 61 384 0.0037 0.54 0.36 0.821 0.0443 A 0.43 G 0.57hCV1361979 rs25683 ACAT2 endpt1 AG + AA 97 851 104 820 0.4633 0.9 0.6841.189 0.0443 A 0.43 G 0.57 hCV1375141 rs1881420 ALK endpt1 CC 10 69 6 610.4852 1.43 0.521 3.947 0.0936 C 0.21 T 0.79 hCV1375141 rs1881420 ALKendpt1 CT 33 421 60 399 0.0053 0.55 0.357 0.835 0.0936 C 0.21 T 0.79hCV1375141 rs1881420 ALK endpt1 TT 90 799 99 757 0.3071 0.86 0.648 1.1460.0936 C 0.21 T 0.79 hCV1552894 rs434473 ALOX12 endpt1 GG 16 212 43 2220.0028 0.42 0.234 0.739 0.0162 G 0.42 A 0.58 hCV1552894 rs434473 ALOX12endpt1 GA + AA 116 1073 122 990 0.3177 0.88 0.681 1.133 0.0162 G 0.42 A0.58 hCV1552900 rs1126667 ALOX12 endpt1 AA 16 212 43 223 0.0030 0.420.236 0.744 0.0159 A 0.42 G 0.58 hCV1552900 rs1126667 ALOX12 endpt1 AG +GG 117 1076 122 991 0.3456 0.89 0.687 1.141 0.0159 A 0.42 G 0.58hCV15746640 rs41271951 CTSS endpt1 AA 109 1096 150 1021 0.0032 0.690.539 0.883 0.0177 G 0.08 A 0.92 hCV15746640 rs41271951 CTSS endpt1 GA +GG 24 194 15 193 0.1717 1.57 0.823 2.99 0.0177 G 0.08 A 0.92 hCV15758290rs6716834 LRP2 endpt1 AA 58 635 87 563 0.0030 0.6 0.434 0.843 0.0441 G0.30 A 0.70 hCV15758290 rs6716834 LRP2 endpt1 GA + GG 75 648 78 6460.8294 0.97 0.703 1.326 0.0441 G 0.30 A 0.70 hCV15760070 rs2308911HLA-DPA1 endpt1 TT 7 31 1 38 0.0713 6.88 0.846 56.019 0.0073 T 0.17 A0.83 hCV15760070 rs2308911 HLA-DPA1 endpt1 TA + AA 126 1258 164 11790.0090 0.73 0.582 0.926 0.0073 T 0.17 A 0.83 hCV15851335 rs17610395CPT1A endpt1 CC 111 1123 147 1039 0.0073 0.71 0.558 0.913 0.0891 T 0.07C 0.93 hCV15851335 rs17610395 CPT1A endpt1 TC + TT 21 164 17 176 0.44121.29 0.678 2.437 0.0891 T 0.07 C 0.93 hCV15851779 rs2230009 WRN endpt1AA 0 6 2 4 0.9977 0 0 . 0.0624 A 0.06 G 0.94 hCV15851779 rs2230009 WRNendpt1 AG 20 132 14 129 0.3772 1.36 0.687 2.693 0.0624 A 0.06 G 0.94hCV15851779 rs2230009 WRN endpt1 GG 113 1150 149 1082 0.0103 0.73 0.5690.927 0.0624 A 0.06 G 0.94 hCV15876011 rs2228541 SERPINA6 endpt1 GG 35261 24 239 0.3001 1.32 0.783 2.212 0.0268 G 0.45 T 0.55 hCV15876011rs2228541 SERPINA6 endpt1 GT + TT 96 991 137 951 0.0048 0.69 0.529 0.8920.0268 G 0.45 T 0.55 hCV15954277 rs2236379 PRKCQ endpt1 AA 13 103 3 920.0411 3.7 1.054 12.989 0.0042 A 0.26 G 0.74 hCV15954277 rs2236379 PRKCQendpt1 AG + GG 120 1188 162 1126 0.0054 0.72 0.565 0.906 0.0042 A 0.26 G0.74 hCV15955388 rs2227376 F2RL3 endpt1 CC 132 1247 157 1173 0.0594 0.80.635 1.009 0.0435 T 0.02 C 0.98 hCV15955388 rs2227376 F2RL3 endpt1 TC +TT 1 42 8 42 0.0629 0.14 0.017 1.112 0.0435 T 0.02 C 0.98 hCV15963535rs2228591 NCOA2 endpt1 CC 124 1155 142 1087 0.1293 0.83 0.652 1.0560.0412 G 0.05 C 0.95 hCV15963535 rs2228591 NCOA2 endpt1 GC + GG 8 132 23130 0.0128 0.36 0.161 0.805 0.0412 G 0.05 C 0.95 hCV1600754 rs17288671CXCL9 endpt1 CC 34 396 51 324 0.0099 0.56 0.366 0.872 0.0869 T 0.46 C0.54 hCV1600754 rs17288671 CXCL9 endpt1 TC + TT 99 892 114 893 0.33650.88 0.669 1.147 0.0869 T 0.46 C 0.54 hCV1603697 rs2229475 HSPG2 endpt1CC 122 1141 142 1083 0.1196 0.83 0.648 1.051 0.0985 T 0.06 C 0.94hCV1603697 rs2229475 HSPG2 endpt1 TC + TT 11 148 23 132 0.0253 0.440.215 0.904 0.0985 T 0.06 C 0.94 hCV16044337 rs2569491 KLK14 endpt1 AA 7127 26 114 0.0012 0.25 0.11 0.582 0.0028 A 0.31 G 0.69 hCV16044337rs2569491 KLK14 endpt1 AG + GG 126 1157 138 1095 0.2664 0.87 0.685 1.110.0028 A 0.31 G 0.69 hCV16047108 rs2244008 LAMA2 endpt1 AA 104 1148 1451062 0.0025 0.68 0.527 0.872 0.0174 G 0.06 A 0.94 hCV16047108 rs2244008LAMA2 endpt1 GA + GG 28 140 20 151 0.2238 1.43 0.804 2.537 0.0174 G 0.06A 0.94 hCV16172339 rs2229489 HSPG2 endpt1 AA 121 1140 141 1081 0.11760.82 0.646 1.05 0.0974 T 0.06 A 0.94 hCV16172339 rs2229489 HSPG2 endpt1TA + TT 11 147 23 131 0.0251 0.44 0.214 0.903 0.0974 T 0.06 A 0.94hCV16173091 rs2241883 FABP1 endpt1 CC 18 126 10 136 0.1086 1.88 0.8694.079 0.0148 C 0.32 T 0.68 hCV16173091 rs2241883 FABP1 endpt1 CT + TT115 1164 155 1080 0.0041 0.7 0.552 0.894 0.0148 C 0.32 T 0.68hCV16179493 rs2108622 CYP4F2 endpt1 CC 54 613 90 574 0.0015 0.58 0.4130.811 0.0241 T 0.31 C 0.69 hCV16179493 rs2108622 CYP4F2 endpt1 TC + TT77 670 75 640 0.9145 0.98 0.715 1.351 0.0241 T 0.31 C 0.69 hCV16179628rs2273697 ABCC2 endpt1 AA 1 68 4 28 0.0562 0.12 0.013 1.058 0.0472 A0.20 G 0.80 hCV16179628 rs2273697 ABCC2 endpt1 AG + GG 132 1220 161 11890.0668 0.81 0.641 1.015 0.0472 A 0.20 G 0.80 hCV16182835 rs2274736PTPN21 endpt1 AA 70 555 62 511 0.8609 1.03 0.733 1.451 0.0411 G 0.34 A0.66 hCV16182835 rs2274736 PTPN21 endpt1 GA + GG 62 703 98 684 0.00530.64 0.463 0.874 0.0411 G 0.34 A 0.66 hCV16192174 rs2305948 KDR endpt1GG 96 1043 134 984 0.0052 0.69 0.53 0.895 0.0847 A 0.10 G 0.90hCV16192174 rs2305948 KDR endpt1 AG + AA 37 248 31 232 0.6835 1.1 0.6851.78 0.0847 A 0.10 G 0.90 hCV1647371 rs3025000 VEGFA endpt1 CC 57 600 88529 0.0026 0.6 0.429 0.835 0.0251 T 0.33 C 0.67 hCV1647371 rs3025000VEGFA endpt1 TC + TT 75 662 73 664 0.9194 1.02 0.737 1.403 0.0251 T 0.33C 0.67 hCV1741111 rs1764391 C1orf212 endpt1 TT 12 114 6 97 0.2976 1.680.632 4.486 0.0931 T 0.30 C 0.70 hCV1741111 rs1764391 C1orf212 endpt1TC + CC 121 1174 159 1118 0.0109 0.74 0.581 0.932 0.0931 T 0.30 C 0.70hCV1770462 rs12731981 MPL endpt1 GG 114 1204 153 1141 0.0070 0.72 0.5620.913 0.0818 A 0.03 G 0.97 hCV1770462 rs12731981 MPL endpt1 AG + AA 1882 12 76 0.3614 1.41 0.677 2.918 0.0818 A 0.03 G 0.97 hCV1843175rs3745535 KLK10 endpt1 CC 57 528 59 538 0.9494 0.99 0.687 1.422 0.0787 A0.36 C 0.64 hCV1843175 rs3745535 KLK10 endpt1 AC + AA 75 754 106 6750.0040 0.65 0.482 0.87 0.0787 A 0.36 C 0.64 hCV2038 rs4673 CYBA endpt1GG 44 563 76 520 0.0018 0.55 0.382 0.803 0.0216 A 0.34 G 0.66 hCV2038rs4673 CYBA endpt1 AG + AA 89 728 89 697 0.7717 0.96 0.714 1.284 0.0216A 0.34 G 0.66 hCV2143205 rs9666607 CD44 endpt1 AA 16 125 9 119 0.23011.65 0.729 3.732 0.0524 A 0.32 G 0.68 hCV2143205 rs9666607 CD44 endpt1AG + GG 117 1167 156 1099 0.0072 0.72 0.567 0.915 0.0524 A 0.32 G 0.68hCV22271999 rs2305948 KDR endpt1 CC 96 1041 133 981 0.0060 0.69 0.5320.9 0.0944 T 0.10 C 0.90 hCV22271999 rs2305948 KDR endpt1 TC + TT 37 24831 230 0.7100 1.09 0.679 1.764 0.0944 T 0.10 C 0.90 hCV22274761rs11575194 IGFBP5 endpt1 GG 126 1175 149 1113 0.0831 0.81 0.64 1.0280.0849 A 0.04 G 0.96 hCV22274761 rs11575194 IGFBP5 endpt1 AG + AA 6 10816 100 0.0333 0.36 0.141 0.923 0.0849 A 0.04 G 0.96 hCV22275550rs6836335 SPON2 endpt1 CC 3 15 1 26 0.2235 4.08 0.424 39.314 0.0946 C0.12 T 0.88 hCV22275550 rs6836335 SPON2 endpt1 CT + TT 129 1270 164 11890.0139 0.75 0.594 0.943 0.0946 C 0.12 T 0.88 hCV2230606 rs13268 FBLN1endpt1 AA 124 1224 161 1153 0.0109 0.74 0.584 0.932 0.0281 G 0.02 A 0.98hCV2230606 rs13268 FBLN1 endpt1 GA + GG 9 62 3 63 0.1073 2.93 0.79210.814 0.0281 G 0.02 A 0.98 hCV2276802 rs381418 GBA endpt1 AA 33 354 54313 0.0088 0.56 0.364 0.865 0.0820 C 0.37 A 0.63 hCV2276802 rs381418 GBAendpt1 CA + CC 100 935 110 903 0.3623 0.88 0.673 1.156 0.0820 C 0.37 A0.63 hCV2310409 45474794-rs6 APOA4 endpt1 TT 76 825 107 756 0.0061 0.660.494 0.889 0.1000 A 0.20 T 0.80 hCV2310409 45474794-rs6 APOA4 endpt1AT + AA 56 459 56 450 0.9347 0.98 0.68 1.426 0.1000 A 0.20 T 0.80hCV2485037 rs4904448 SPATA7 endpt1 AA 31 228 23 219 0.4154 1.25 0.732.146 0.0581 A 0.43 G 0.57 hCV2485037 rs4904448 SPATA7 endpt1 AG + GG101 1032 137 965 0.0082 0.71 0.547 0.914 0.0581 A 0.43 G 0.57 hCV2503034rs1132356 BAIAP3 endpt1 AA 0 16 3 4 0.9978 0 0 . 0.0411 A 0.11 C 0.89hCV2503034 rs1132356 BAIAP3 endpt1 AC 34 258 35 219 0.3764 0.81 0.5041.296 0.0411 A 0.11 C 0.89 hCV2503034 rs1132356 BAIAP3 endpt1 CC 97 1010126 985 0.0498 0.77 0.589 1 0.0411 A 0.11 C 0.89 hCV2531086 rs10406069CD22 endpt1 AA 7 52 2 47 0.1378 3.29 0.682 15.892 0.0460 A 0.21 G 0.79hCV2531086 rs10406069 CD22 endpt1 AG + GG 124 1236 163 1167 0.0081 0.730.577 0.921 0.0460 A 0.21 G 0.79 hCV2536595 rs704 VTN endpt1 GG 44 35134 381 0.1617 1.38 0.88 2.154 0.0027 A 0.47 G 0.53 hCV2536595 rs704 VTNendpt1 AG + AA 89 940 131 837 0.0005 0.62 0.475 0.814 0.0027 A 0.47 G0.53 hCV25472345 rs4900072 C14orf159 endpt1 TT 8 154 29 160 0.0036 0.310.143 0.683 0.0075 T 0.34 C 0.66 hCV25472345 rs4900072 C14orf159 endpt1TC + CC 124 1108 130 1029 0.3416 0.89 0.694 1.135 0.0075 T 0.34 C 0.66hCV25472673 rs1805081 NPC1 endpt1 TT 59 484 47 455 0.4153 1.17 0.7991.72 0.0080 C 0.39 T 0.61 hCV25472673 rs1805081 NPC1 endpt1 CT + CC 74803 117 761 0.0010 0.61 0.459 0.822 0.0080 C 0.39 T 0.61 hCV25473098rs2241883 FABP1 endpt1 GG 18 124 11 137 0.1440 1.75 0.826 3.704 0.0227 G0.31 A 0.69 hCV25473098 rs2241883 FABP1 endpt1 GA + AA 115 1165 152 10710.0055 0.71 0.557 0.904 0.0227 G 0.31 A 0.69 hCV25474101 rs41554412 MICAendpt1 CC 7 25 2 32 0.0951 3.81 0.792 18.358 0.0195 C 0.15 T 0.85hCV25474101 rs41554412 MICA endpt1 CT + TT 126 1266 163 1184 0.0094 0.730.582 0.927 0.0195 C 0.15 T 0.85 hCV25591528 CD163 endpt1 GG 114 994 128956 0.2637 0.87 0.673 1.115 0.0417 A 0.12 G 0.88 hCV25591528 CD163endpt1 AG + AA 19 296 37 262 0.0065 0.46 0.267 0.807 0.0417 A 0.12 G0.88 hCV25596880 rs4647297 CASP2 endpt1 CC 2 3 0 6 0.9977 1E+08 0 .0.0713 C 0.06 G 0.94 hCV25596880 rs4647297 CASP2 endpt1 CG 12 136 12 1370.9890 0.99 0.447 2.214 0.0713 C 0.06 G 0.94 hCV25596880 rs4647297 CASP2endpt1 GG 118 1150 153 1072 0.0107 0.73 0.575 0.93 0.0713 C 0.06 G 0.94hCV25598594 rs41274768 CR1 endpt1 GG 132 1226 154 1167 0.1016 0.82 0.6531.039 0.0028 A 0.02 G 0.98 hCV25598594 rs41274768 CR1 endpt1 AG + AA 165 11 50 0.0150 0.08 0.01 0.61 0.0028 A 0.02 G 0.98 hCV25603879rs11542844 SCNN1A endpt1 CC 122 1200 160 1126 0.0082 0.73 0.575 0.9210.0527 T 0.03 C 0.97 hCV25603879 rs11542844 SCNN1A endpt1 TC + TT 11 895 85 0.2080 1.97 0.685 5.68 0.0527 T 0.03 C 0.97 hCV25605897 rs11568563SLCO1A2 endpt1 TT 126 1140 144 1088 0.1708 0.85 0.666 1.075 0.0166 G0.06 T 0.94 hCV25605897 rs11568563 SLCO1A2 endpt1 GT + GG 7 150 20 1260.0065 0.3 0.128 0.716 0.0166 G 0.06 T 0.94 hCV25607193 FLNB endpt1 TT127 1258 164 1191 0.0129 0.75 0.591 0.94 0.0477 C 0.01 T 0.99hCV25607193 FLNB endpt1 CT + CC 6 33 1 27 0.1685 4.42 0.533 36.7530.0477 C 0.01 T 0.99 hCV25608818 SLC10A2 endpt1 GG 126 1258 162 11760.0110 0.74 0.586 0.933 0.0206 A 0.01 G 0.99 hCV25608818 SLC10A2 endpt1AG + AA 7 32 2 40 0.0832 4.01 0.833 19.312 0.0206 A 0.01 G 0.99hCV25610470 rs34075341 C9orf47 endpt1 GG 128 1182 151 1128 0.0946 0.820.646 1.035 0.0431 A 0.04 G 0.96 hCV25610470 rs34075341 C9orf47 endpt1AG + AA 4 103 13 87 0.0235 0.27 0.089 0.84 0.0431 A 0.04 G 0.96hCV25610774 rs8176748 endpt1 TT 5 57 2 67 0.2456 2.64 0.512 13.6440.0989 T 0.23 C 0.77 hCV25610774 rs8176748 endpt1 TC + CC 127 1231 1631150 0.0116 0.74 0.588 0.935 0.0989 T 0.23 C 0.77 hCV25610819 rs8176740endpt1 TT 5 58 2 70 0.2297 2.73 0.53 14.102 0.0925 T 0.23 A 0.77hCV25610819 rs8176740 endpt1 TA + AA 128 1225 163 1139 0.0122 0.74 0.590.937 0.0925 T 0.23 A 0.77 hCV25614016 rs7607759 CAPN10 endpt1 AA 87 915130 840 0.0010 0.63 0.482 0.83 0.0072 G 0.16 A 0.84 hCV25614016rs7607759 CAPN10 endpt1 GA + GG 46 374 35 374 0.2727 1.28 0.824 1.9850.0072 G 0.16 A 0.84 hCV25617571 rs2232580 LBP endpt1 CC 117 1090 1321052 0.2572 0.87 0.675 1.111 0.0208 T 0.08 C 0.92 hCV25617571 rs2232580LBP endpt1 TC + TT 16 200 33 165 0.0037 0.41 0.227 0.751 0.0208 T 0.08 C0.92 hCV25623265 rs3746638 SIGLEC1 endpt1 GG 14 288 40 279 0.0008 0.350.193 0.65 0.0039 G 0.48 A 0.52 hCV25623265 rs3746638 SIGLEC1 endpt1GA + AA 118 1000 125 936 0.3626 0.89 0.692 1.144 0.0039 G 0.48 A 0.52hCV25629396 rs3729823 MYH7 endpt1 GG 125 1260 163 1166 0.0064 0.72 0.5730.913 0.0011 C 0.01 G 0.99 hCV25629396 rs3729823 MYH7 endpt1 CG + CC 726 1 48 0.0266 10.7 1.317 87.094 0.0011 C 0.01 G 0.99 hCV25629476rs2427284 LAMA5 endpt1 GG 111 1158 150 1095 0.0071 0.71 0.558 0.9120.0602 A 0.05 G 0.95 hCV25629476 rs2427284 LAMA5 endpt1 AG + AA 22 13114 121 0.3104 1.41 0.724 2.765 0.0602 A 0.05 G 0.95 hCV25629492 rs944895LAMA5 endpt1 AA 66 511 71 513 0.6944 0.94 0.669 1.307 0.0916 G 0.36 A0.64 hCV25629492 rs944895 LAMA5 endpt1 GA + GG 64 773 94 696 0.0043 0.630.458 0.865 0.0916 G 0.36 A 0.64 hCV25629888 rs11539441 TIMP2 endpt1 GG7 30 3 34 0.1786 2.53 0.654 9.788 0.0742 G 0.17 C 0.83 hCV25629888rs11539441 TIMP2 endpt1 GC + CC 125 1261 161 1184 0.0120 0.74 0.5870.936 0.0742 G 0.17 C 0.83 hCV25652744 rs1127525 USP21 endpt1 AA 1 0 0 41.0000 4E+12 0 . 0.0261 A 0.05 C 0.95 hCV25652744 rs1127525 USP21 endpt1AC 5 113 15 107 0.0373 0.34 0.124 0.939 0.0261 A 0.05 C 0.95 hCV25652744rs1127525 USP21 endpt1 CC 127 1153 145 1082 0.1210 0.83 0.653 1.0510.0261 A 0.05 C 0.95 hCV1026586 rs673548 APOB endpt1 GA + GG 127 1203163 1147 0.0160 0.75 0.60 0.95 0.0780 A 0.22 G 0.78 hCV1026586 rs673548APOB endpt1 AA 9 59 4 58 0.2000 2.15 0.66 6.97 0.0780 A 0.22 G 0.78hCV11466848 rs1805419 BAX endpt1 AG + AA 53 620 93 563 0.0003 0.54 0.380.75 0.0020 A 0.28 G 0.72 hCV11466848 rs1805419 BAX endpt1 GG 83 645 74643 0.5200 1.11 0.81 1.52 0.0020 A 0.28 G 0.72 hCV11513719 rs2967605ELAVL1 endpt1 TC + TT 40 425 67 372 0.0019 0.54 0.36 0.80 0.0180 C 0.82T 0.18 hCV11513719 rs2967605 ELAVL1 endpt1 CC 95 832 99 829 0.7800 0.960.73 1.27 0.0180 C 0.82 T 0.18 hCV1323634 rs287475 endpt1 TC + TT 1061034 149 980 0.0031 0.69 0.54 0.88 0.0074 C 0.43 T 0.57 hCV1323634rs287475 endpt1 CC 30 229 18 225 0.1000 1.63 0.91 2.93 0.0074 C 0.43 T0.57 hCV1323669 rs287354 endpt1 GA + GG 104 1023 144 968 0.0048 0.700.54 0.89 0.0190 A 0.44 G 0.56 hCV1323669 rs287354 endpt1 AA 32 244 22239 0.2100 1.42 0.82 2.44 0.0190 A 0.44 G 0.56 hCV1729928 rs10509384KCNMA1 endpt1 AG + AA 117 1119 153 1043 0.0096 0.73 0.57 0.93 0.0880 A0.66 G 0.34 hCV1729928 rs10509384 KCNMA1 endpt1 GG 18 142 14 158 0.36001.39 0.69 2.79 0.0880 A 0.66 G 0.34 hCV1948599 rs504527 CSMD2 endpt1CA + CC 92 989 129 920 0.0041 0.68 0.52 0.88 0.0320 A 0.49 C 0.51hCV1948599 rs504527 CSMD2 endpt1 AA 44 275 38 283 0.4600 1.18 0.76 1.820.0320 A 0.49 C 0.51 hCV2554615 rs2522057 LOC441108 endpt1 CG + CC 1071046 146 998 0.0098 0.72 0.56 0.92 0.0580 C 0.58 G 0.42 hCV2554615rs2522057 LOC441108 endpt1 GG 29 216 20 208 0.3900 1.28 0.73 2.27 0.0580C 0.58 G 0.42 hCV2554721 rs7315519 RPH3A endpt1 AG + AA 84 911 130 8440.0005 0.62 0.47 0.81 0.0015 A 0.46 G 0.54 hCV2554721 rs7315519 RPH3Aendpt1 GG 52 355 37 361 0.1200 1.39 0.91 2.12 0.0015 A 0.46 G 0.54hCV260164 rs6754295 endpt1 TG + TT 127 1195 163 1138 0.0160 0.75 0.600.95 0.0720 G 0.24 T 0.76 hCV260164 rs6754295 endpt1 GG 9 68 4 68 0.19002.19 0.67 7.10 0.0720 G 0.24 T 0.76 hCV2762168 rs3939286 endpt1 TC + TT62 592 91 531 0.0052 0.63 0.46 0.87 0.0600 C 0.74 T 0.26 hCV2762168rs3939286 endpt1 CC 74 673 76 673 0.8700 0.97 0.71 1.34 0.0600 C 0.74 T0.26 hCV2781953 rs6021931 endpt1 GT + GG 127 1214 161 1158 0.0220 0.760.6 0.96 0.0870 G 0.81 T 0.19 hCV2781953 rs6021931 endpt1 TT 9 49 4 460.2000 2.15 0.66 7.02 0.0870 G 0.81 T 0.19 hCV29011391 rs7557067 endpt1AG + AA 126 1191 163 1139 0.0150 0.75 0.59 0.95 0.0790 A 0.76 G 0.24hCV29011391 rs7557067 endpt1 GG 9 69 4 67 0.2100 2.13 0.66 6.91 0.0790 A0.76 G 0.24 hCV29135108 rs6743779 KLF7 endpt1 CA + CC 61 661 103 6330.0009 0.58 0.43 0.80 0.0076 A 0.69 C 0.31 hCV29135108 rs6743779 KLF7endpt1 AA 74 601 64 572 0.5900 1.10 0.78 1.53 0.0076 A 0.69 C 0.31hCV30264691 rs10508518 CUBN endpt1 TG + TT 121 1148 157 1087 0.0140 0.740.59 0.94 0.0910 G 0.30 T 0.70 hCV30264691 rs10508518 CUBN endpt1 GG 15111 10 116 0.3000 1.53 0.69 3.41 0.0910 G 0.30 T 0.70 hCV30606396rs10438978 endpt1 TC + TT 40 428 62 375 0.0074 0.58 0.39 0.86 0.0650 C0.82 T 0.18 hCV30606396 rs10438978 endpt1 CC 96 834 105 830 0.5400 0.920.70 1.21 0.0650 C 0.82 T 0.18 hCV31237961 rs11950562 SLC22A4 endpt1AC + AA 101 986 143 936 0.0046 0.69 0.54 0.89 0.0260 A 0.53 C 0.47hCV31237961 rs11950562 SLC22A4 endpt1 CC 35 279 24 268 0.3100 1.31 0.782.2 0.0260 A 0.53 C 0.47 hCV3168675 rs469930 endpt1 GA + GG 77 766 109709 0.0066 0.67 0.5 0.89 0.0790 A 0.64 G 0.36 hCV3168675 rs469930 endpt1AA 59 499 58 495 0.9500 1.01 0.7 1.45 0.0790 A 0.64 G 0.36 hCV3170445rs272893 SLC22A4 endpt1 TC + TT 81 779 121 732 0.0032 0.65 0.49 0.870.0260 C 0.61 T 0.39 hCV3170445 rs272893 SLC22A4 endpt1 CC 55 487 46 4740.5400 1.13 0.76 1.67 0.0260 C 0.61 T 0.39 hCV3170459 rs1050152 SLC22A4endpt1 CT + CC 105 1038 145 989 0.0079 0.71 0.55 0.91 0.0550 C 0.58 T0.42 hCV3170459 rs1050152 SLC22A4 endpt1 TT 31 223 22 217 0.4200 1.250.72 2.16 0.0550 C 0.58 T 0.42 hCV3242919 rs486394 endpt1 AC + AA 1201158 159 1110 0.0110 0.74 0.58 0.93 0.0490 A 0.71 C 0.29 hCV3242919rs486394 endpt1 CC 16 104 8 96 0.1800 1.78 0.76 4.17 0.0490 A 0.71 C0.29 hCV3242952 rs2000571 endpt1 AG + AA 42 464 74 448 0.0035 0.57 0.390.83 0.0320 A 0.21 G 0.79 hCV3242952 rs2000571 endpt1 GG 94 799 93 7570.7700 0.96 0.72 1.28 0.0320 A 0.21 G 0.79 hCV610861 rs636887 endpt1TC + TT 108 1017 146 973 0.0110 0.72 0.56 0.93 0.0900 C 0.43 T 0.57hCV610861 rs636887 endpt1 CC 28 247 21 233 0.4800 1.23 0.7 2.16 0.0900 C0.43 T 0.57 hCV7501549 rs1467412 ATP9A endpt1 CT + CC 93 947 132 9030.0063 0.69 0.53 0.9 0.0620 C 0.50 T 0.50 hCV7501549 rs1467412 ATP9Aendpt1 TT 43 319 35 303 0.5800 1.13 0.73 1.77 0.0620 C 0.50 T 0.50hCV7537517 rs1501908 endpt1 CG + CC 117 1087 156 1041 0.0100 0.73 0.580.93 0.0320 C 0.64 G 0.36 hCV7537517 rs1501908 endpt1 GG 19 175 10 1650.1500 1.75 0.82 3.77 0.0320 C 0.64 G 0.36 hCV7910239 rs1541296 FVT1endpt1 AG + AA 118 1111 152 1041 0.0140 0.74 0.58 0.94 0.0850 A 0.66 G0.34 hCV7910239 rs1541296 FVT1 endpt1 GG 18 147 14 163 0.3200 1.43 0.712.87 0.0850 A 0.66 G 0.34 hCV8420416 rs719909 PANK1 endpt1 CT + CC 1311236 165 1164 0.0200 0.76 0.61 0.96 0.0770 C 0.84 T 0.16 hCV8420416rs719909 PANK1 endpt1 TT 5 26 2 41 0.1500 3.29 0.64 16.97 0.0770 C 0.84T 0.16 hCV8785827 rs992969 IL33 endpt1 AG + AA 61 591 91 527 0.0038 0.620.45 0.86 0.0430 A 0.26 G 0.74 hCV8785827 rs992969 IL33 endpt1 GG 75 67576 677 0.9400 0.99 0.72 1.36 0.0430 A 0.26 G 0.74 hCV8892418 rs901746ACP2 endpt1 GA + GG 53 630 87 593 0.0024 0.59 0.42 0.83 0.0220 A 0.71 G0.29 hCV8892418 rs901746 ACP2 endpt1 AA 83 632 80 613 0.9600 1.01 0.741.37 0.0220 A 0.71 G 0.29 hCV11678789 rs7219148 endpt1 TG + GG 111 918116 905 0.6900 0.95 0.73 1.23 0.0058 G 0.48 T 0.52 hCV11678789 rs7219148endpt1 TT 25 348 51 301 0.0007 0.44 0.27 0.71 0.0058 G 0.48 T 0.52hCV11864162 rs1167998 DOCK7 endpt1 AC + CC 84 692 90 701 0.7400 0.950.71 1.28 0.0660 A 0.66 C 0.34 hCV11864162 rs1167998 DOCK7 endpt1 AA 52570 76 504 0.0074 0.62 0.43 0.88 0.0660 A 0.66 C 0.34 hCV1239369rs275982 endpt1 CA + AA 88 713 90 698 0.7300 0.95 0.71 1.27 0.0510 A0.35 C 0.65 hCV1239369 rs275982 endpt1 CC 48 552 77 508 0.0051 0.6 0.420.86 0.0510 A 0.35 C 0.65 hCV1488444 rs10164405 endpt1 TG + GG 129 1159148 1096 0.1400 0.84 0.66 1.06 0.0910 G 0.71 T 0.29 hCV1488444rs10164405 endpt1 TT 7 103 19 107 0.0240 0.37 0.15 0.88 0.0910 G 0.71 T0.29 hCV1489995 rs4013819 LOC392281 endpt1 GC + CC 120 1076 133 10350.2900 0.88 0.68 1.12 0.0440 C 0.63 G 0.37 hCV1489995 rs4013819LOC392281 endpt1 GG 16 185 34 170 0.0090 0.45 0.25 0.82 0.0440 C 0.63 G0.37 hCV15870728 rs2943245 C10orf64 endpt1 CT + TT 106 922 112 8680.4000 0.89 0.68 1.16 0.0890 C 0.53 T 0.47 hCV15870728 rs2943245C10orf64 endpt1 CC 30 340 55 338 0.0130 0.57 0.36 0.89 0.0890 C 0.53 T0.47 hCV1802755 rs7764347 RFXDC1 endpt1 CT + TT 134 1216 158 1165 0.09200.82 0.65 1.03 0.0880 C 0.18 T 0.82 hCV1802755 rs7764347 RFXDC1 endpt1CC 2 47 9 40 0.0470 0.21 0.05 0.98 0.0880 C 0.18 T 0.82 hCV2557331rs233716 RPH3A endpt1 CT + TT 118 1029 133 1001 0.2600 0.87 0.68 1.110.0830 C 0.42 T 0.58 hCV2557331 rs233716 RPH3A endpt1 CC 18 235 33 2030.0190 0.5 0.28 0.89 0.0830 C 0.42 T 0.58 hCV2632070 rs714052 BAZ1Bendpt1 AG + GG 40 289 30 263 0.4300 1.21 0.75 1.94 0.0400 A 0.88 G 0.12hCV2632070 rs714052 BAZ1B endpt1 AA 96 974 137 940 0.0050 0.69 0.53 0.890.0400 A 0.88 G 0.12 hCV2632498 rs3812316 MLXIPL endpt1 CG + GG 40 29733 277 0.6200 1.12 0.71 1.78 0.0780 C 0.87 G 0.13 hCV2632498 rs3812316MLXIPL endpt1 CC 96 969 134 929 0.0076 0.7 0.54 0.91 0.0780 C 0.87 G0.13 hCV2632544 rs17145738 endpt1 CT + TT 41 283 31 271 0.3400 1.25 0.792.00 0.0230 C 0.88 T 0.12 hCV2632544 rs17145738 endpt1 CC 95 983 136 9360.0037 0.68 0.52 0.88 0.0230 C 0.88 T 0.12 hCV28974083 rs8032553C15orf42 endpt1 GA + AA 105 902 116 899 0.4500 0.90 0.69 1.18 0.0510 A0.48 G 0.52 hCV28974083 rs8032553 C15orf42 endpt1 GG 31 360 51 3060.0067 0.54 0.35 0.84 0.0510 A 0.48 G 0.52 hCV31145250 rs10889353 DOCK7endpt1 AC + CC 84 685 87 687 0.8600 0.97 0.72 1.31 0.0450 A 0.66 C 0.34hCV31145250 rs10889353 DOCK7 endpt1 AA 52 575 79 519 0.0053 0.61 0.430.86 0.0450 A 0.66 C 0.34 hCV31528409 rs7635061 endpt1 AG + GG 74 606 74587 0.8400 0.97 0.7 1.34 0.0850 A 0.71 G 0.29 hCV31528409 rs7635061endpt1 AA 62 659 92 619 0.0085 0.65 0.47 0.9 0.0850 A 0.71 G 0.29hCV31954792 rs6477693 C9orf4 endpt1 CA + AA 129 1163 148 1103 0.14000.84 0.66 1.06 0.0830 A 0.72 C 0.28 hCV31954792 rs6477693 C9orf4 endpt1CC 7 103 19 101 0.0280 0.38 0.16 0.9 0.0830 A 0.72 C 0.28 hCV461035rs7746448 endpt1 TC + CC 89 785 99 796 0.5300 0.91 0.69 1.21 0.0970 C0.40 T 0.60 hCV461035 rs7746448 endpt1 TT 47 481 68 410 0.0094 0.61 0.420.89 0.0970 C 0.40 T 0.60 hCV601961 rs568654 ZNF568 endpt1 AG + GG 1181072 135 1040 0.2200 0.86 0.67 1.10 0.0950 A 0.38 G 0.62 hCV601961rs568654 ZNF568 endpt1 AA 18 190 32 166 0.0210 0.51 0.28 0.90 0.0950 A0.38 G 0.62 hCV8785824 rs1412426 endpt1 AC + CC 128 1137 142 1080 0.23000.86 0.68 1.1 0.0200 A 0.33 C 0.67 hCV8785824 rs1412426 endpt1 AA 8 12725 122 0.0060 0.33 0.15 0.73 0.0200 A 0.33 C 0.67 hCV9581635 rs1748195DOCK7 endpt1 CG + GG 84 687 88 694 0.8500 0.97 0.72 1.31 0.0440 C 0.66 G0.34 hCV9581635 rs1748195 DOCK7 endpt1 CC 52 575 78 511 0.0051 0.61 0.430.86 0.0440 C 0.66 G 0.34 hCV9588862 rs995000 DOCK7 endpt1 CT + TT 84688 88 683 0.7600 0.95 0.71 1.29 0.0570 C 0.66 T 0.34 hCV9588862rs995000 DOCK7 endpt1 CC 52 577 79 523 0.0057 0.61 0.43 0.87 0.0570 C0.66 T 0.34 hDV76976592 rs4149274 ABCA1 endpt1 GA + AA 84 705 83 6690.8100 0.96 0.71 1.31 0.0540 A 0.34 G 0.66 hDV76976592 rs4149274 ABCA1endpt1 GG 52 557 84 537 0.0057 0.61 0.43 0.87 0.0540 A 0.34 G 0.66hCV11568668 rs1317538 KCNQ5 endpt1 AA 43 324 49 277 0.2300 0.78 0.521.17 0.0343 A 0.49 G 0.51 hCV11568668 rs1317538 KCNQ5 endpt1 AG 70 60767 603 0.9100 1.02 0.73 1.43 0.0343 A 0.49 G 0.51 hCV11568668 rs1317538KCNQ5 endpt1 GG 23 336 50 328 0.0028 0.47 0.29 0.77 0.0343 A 0.49 G 0.51hCV2221541 rs739161 endpt1 CC 7 121 17 80 0.0066 0.30 0.12 0.71 0.0367 C0.29 T 0.71 hCV2221541 rs739161 endpt1 TC 55 492 60 535 0.9400 0.99 0.681.42 0.0367 C 0.29 T 0.71 hCV2221541 rs739161 endpt1 TT 74 649 90 5910.0910 0.77 0.56 1.04 0.0367 C 0.29 T 0.71 hCV601962 rs544543 ZNF568endpt1 AA 44 522 66 457 0.0088 0.60 0.41 0.88 0.0198 A 0.62 G 0.38hCV601962 rs544543 ZNF568 endpt1 GA 71 545 69 579 0.6100 1.09 0.78 1.520.0198 A 0.62 G 0.38 hCV601962 rs544543 ZNF568 endpt1 GG 18 191 32 1680.0240 0.51 0.29 0.92 0.0198 A 0.62 G 0.38 hCV8369472 rs1447351 MTNR1Bendpt1 GG 42 347 59 322 0.0610 0.68 0.46 1.02 0.0471 A 0.48 G 0.52hCV8369472 rs1447351 MTNR1B endpt1 GA 65 586 65 632 0.7100 1.07 0.761.50 0.0471 A 0.48 G 0.52 hCV8369472 rs1447351 MTNR1B endpt1 AA 29 33043 252 0.0088 0.53 0.33 0.85 0.0471 A 0.48 G 0.52 hCV22303 rs4552916endpt1 AA 86 788 95 755 0.3600 0.87 0.65 1.17 0.0391 A 0.78 G 0.22hCV22303 rs4552916 endpt1 GA 37 408 65 383 0.0038 0.55 0.37 0.82 0.0391A 0.78 G 0.22 hCV22303 rs4552916 endpt1 GG 13 70 7 68 0.2400 1.73 0.694.33 0.0391 A 0.78 G 0.22 hCV601946 rs524802 ZNF568 endpt1 AA 17 175 29156 0.0410 0.54 0.29 0.97 0.0203 A 0.37 G 0.63 hCV601946 rs524802 ZNF568endpt1 AG 74 554 70 578 0.5700 1.1 0.79 1.53 0.0203 A 0.37 G 0.63hCV601946 rs524802 ZNF568 endpt1 GG 45 536 68 471 0.0077 0.6 0.41 0.870.0203 A 0.37 G 0.63 hCV922535 rs748065 endpt1 AA 74 611 76 587 0.73000.95 0.69 1.3 0.0842 A 0.70 G 0.30 hCV922535 rs748065 endpt1 GA 48 54181 520 0.0032 0.58 0.41 0.84 0.0842 A 0.70 G 0.30 hCV922535 rs748065endpt1 GG 14 114 10 98 0.7000 1.17 0.52 2.63 0.0842 A 0.70 G 0.30hDV70797856 rs17006217 endpt1 CC 2 14 0 13 1.0000 1E+09 0 Inf 0.0397 C0.11 T 0.89 hDV70797856 rs17006217 endpt1 CT 25 255 45 231 0.0084 0.520.32 0.84 0.0397 C 0.11 T 0.89 hDV70797856 rs17006217 endpt1 TT 109 997122 962 0.3000 0.87 0.67 1.13 0.0397 C 0.11 T 0.89 hCV11856381 rs2197089rmi AG + AA 84 1006 129 970 0.0018 0.65 0.49 0.85 0.0420 A 0.54 G 0.46hCV11856381 rs2197089 rmi GG 27 279 19 253 0.4300 1.26 0.70 2.27 0.0420A 0.54 G 0.46 hCV16140621 rs2156552 rmi AT + AA 30 416 53 371 0.00450.52 0.33 0.82 0.0810 A 0.17 T 0.83 hCV16140621 rs2156552 rmi TT 81 87695 854 0.2500 0.84 0.63 1.13 0.0810 A 0.17 T 0.83 hCV1682755 rs9424977NEGR1 rmi CT + CC 73 941 112 893 0.0021 0.63 0.47 0.85 0.0780 C 0.48 T0.52 hCV1682755 rs9424977 NEGR1 rmi TT 38 347 36 331 0.9200 1.02 0.651.62 0.0780 C 0.48 T 0.52 hCV27480853 rs3766430 SSBP3 rmi TC + TT 811029 124 992 0.0022 0.65 0.49 0.85 0.0820 C 0.44 T 0.56 hCV27480853rs3766430 SSBP3 rmi CC 30 262 24 233 0.7200 1.10 0.64 1.88 0.0820 C 0.44T 0.56 hCV2948766 rs4684343 CNTN4 rmi GA + GG 85 1042 129 1010 0.00220.65 0.50 0.86 0.0660 A 0.43 G 0.57 hCV2948766 rs4684343 CNTN4 rmi AA 25244 18 213 0.5200 1.22 0.67 2.24 0.0660 A 0.43 G 0.57 hCV30534667rs4996259 MAGI2 rmi AG + AA 47 667 79 595 0.0012 0.55 0.38 0.79 0.0330 A0.30 G 0.70 hCV30534667 rs4996259 MAGI2 rmi GG 64 624 69 630 0.7300 0.940.67 1.32 0.0330 A 0.30 G 0.70 hCV30764105 rs12521915 ITGA2 rmi GC + GG57 800 94 727 0.0008 0.57 0.41 0.79 0.0240 C 0.63 G 0.37 hCV30764105rs12521915 ITGA2 rmi CC 54 491 54 498 0.9700 1.01 0.69 1.47 0.0240 C0.63 G 0.37 hCV11231076 rs4857855 rmi CT + TT 46 405 42 414 0.6200 1.110.73 1.69 0.0130 C 0.82 T 0.18 hCV11231076 rs4857855 rmi CC 65 885 106809 0.0005 0.58 0.42 0.79 0.0130 C 0.82 T 0.18 hCV11466079 rs157580TOMM40 rmi GA + AA 98 1081 119 1029 0.1000 0.80 0.61 1.04 0.0830 A 0.61G 0.39 hCV11466079 rs157580 TOMM40 rmi GG 13 207 29 195 0.0120 0.43 0.230.83 0.0830 A 0.61 G 0.39 hCV11592758 rs6265 BDNF rmi CT + TT 48 434 44407 0.9000 1.03 0.68 1.54 0.0360 C 0.82 T 0.18 hCV11592758 rs6265 BDNFrmi CC 61 880 101 830 0.0010 0.59 0.43 0.81 0.0360 C 0.82 T 0.18hCV11703905 rs1169301 TCF1 rmi CT + TT 67 661 72 632 0.5000 0.89 0.641.25 0.0730 C 0.69 T 0.31 hCV11703905 rs1169301 TCF1 rmi CC 44 627 76593 0.0026 0.57 0.39 0.82 0.0730 C 0.69 T 0.31 hCV2195496 rs4982795 rmiCT + TT 92 1020 112 989 0.1300 0.81 0.61 1.06 0.0950 C 0.44 T 0.56hCV2195496 rs4982795 rmi CC 18 266 35 234 0.0099 0.47 0.27 0.84 0.0950 C0.44 T 0.56 hCV28960526 rs6853079 TSPAN5 rmi AT + TT 51 495 49 4940.8400 1.04 0.70 1.54 0.0220 A 0.77 T 0.23 hCV28960526 rs6853079 TSPAN5rmi AA 60 796 99 732 0.0007 0.57 0.42 0.79 0.0220 A 0.77 T 0.23hCV29480044 rs10516433 TSPAN5 rmi CT + TT 51 491 49 494 0.8100 1.05 0.711.55 0.0210 C 0.78 T 0.22 hCV29480044 rs10516433 TSPAN5 rmi CC 60 795 99733 0.0008 0.58 0.42 0.79 0.0210 C 0.78 T 0.22 hCV30136303 rs6914527 rmiGC + CC 77 797 85 813 0.6000 0.92 0.68 1.25 0.0130 C 0.40 G 0.60hCV30136303 rs6914527 rmi GG 34 493 63 412 0.0005 0.48 0.31 0.72 0.0130C 0.40 G 0.60 hCV30454150 rs10516434 TSPAN5 rmi CT + TT 51 489 49 4910.8200 1.05 0.71 1.55 0.0200 C 0.78 T 0.22 hCV30454150 rs10516434 TSPAN5rmi CC 60 799 99 734 0.0007 0.57 0.42 0.79 0.0200 C 0.78 T 0.22hCV487868 rs6439132 rmi TC + CC 60 573 63 563 0.7200 0.94 0.66 1.340.0490 C 0.26 T 0.74 hCV487868 rs6439132 rmi TT 51 718 85 662 0.00150.57 0.40 0.81 0.0490 C 0.26 T 0.74 hCV904974 rs439401 rmi TC + CC 1011090 122 1025 0.0790 0.79 0.61 1.03 0.0980 C 0.61 T 0.39 hCV904974rs439401 rmi TT 10 194 26 199 0.0160 0.41 0.20 0.85 0.0980 C 0.61 T 0.39hCV15954645 rs2954029 rmi AA 36 376 31 344 0.8600 1.04 0.65 1.69 0.0421A 0.53 T 0.47 hCV15954645 rs2954029 rmi AT 46 613 89 601 0.0004 0.530.37 0.75 0.0421 A 0.53 T 0.47 hCV15954645 rs2954029 rmi TT 28 296 28278 0.8200 0.94 0.56 1.59 0.0421 A 0.53 T 0.47 hCV29684678 rs10486788rmi CC 9 89 6 105 0.3000 1.72 0.61 4.83 0.0984 C 0.28 G 0.72 hCV29684678rs10486788 rmi CG 40 526 67 481 0.0045 0.57 0.38 0.84 0.0984 C 0.28 G0.72 hCV29684678 rs10486788 rmi GG 62 672 74 637 0.2000 0.80 0.57 1.120.0984 C 0.28 G 0.72 hCV621313 rs471364 C9orf52 rmi CC 2 16 1 24 0.43002.64 0.24 29.12 0.0972 C 0.13 T 0.87 hCV621313 rs471364 C9orf52 rmi CT20 288 41 263 0.0048 0.46 0.27 0.79 0.0972 C 0.13 T 0.87 hCV621313rs471364 C9orf52 rmi TT 89 984 106 936 0.1500 0.81 0.61 1.08 0.0972 C0.13 T 0.87 hDV70938014 rs17321515 rmi AA 34 363 31 328 0.9200 0.98 0.601.59 0.0770 A 0.52 G 0.48 hDV70938014 rs17321515 rmi AG 47 620 88 6120.0009 0.55 0.38 0.78 0.0770 A 0.52 G 0.48 hDV70938014 rs17321515 rmi GG30 309 29 287 0.8800 0.96 0.58 1.60 0.0770 A 0.52 G 0.48 hCV11446935rs2409722 XKR6 rmi GG 39 325 39 337 0.8400 1.05 0.67 1.63 0.0560 G 0.51T 0.49 hCV11446935 rs2409722 XKR6 rmi GT + TT 72 960 109 888 0.0019 0.620.46 0.84 0.0560 G 0.51 T 0.49 hCV10048483 rs2145270 rmi CC 22 187 16166 0.5000 1.25 0.66 2.38 0.0730 C 0.38 T 0.62 hCV10048483 rs2145270 rmiCT + TT 89 1103 132 1059 0.0023 0.66 0.50 0.86 0.0730 C 0.38 T 0.62

TABLE 22 SNPs Associated with Risk of CHD in Placebo Arm of CARE E-TOTAL Allele 2 VENTS PA- Al- Al- Al- (refer- (pla- TIENTS lele lele leleence cebo (placebo 1 2 Mod- End- hCV rs gene symbol 1 allele) arm) arm)Freq. Freq. HR HR95L HR95U P value el point hCV11513719 rs2967605 ELAVL1T C 166 1367 0.18 0.82 1.49 1.09 2.03 0.012 dom endpt1 hCV1323634rs287475 T C 167 1372 0.57 0.43 1.90 1.17 3.10 0.01 dom endpt1hCV1323669 rs287354 G A 166 1373 0.56 0.44 1.62 1.04 2.54 0.034 domendpt1 hCV1729928 rs10509384 KCNMA1 A G 167 1368 0.66 0.34 1.59 0.922.75 0.096 dom endpt1 hCV2221541 rs739161 T C 167 1373 0.71 0.29 0.650.39 1.07 0.087 dom endpt1 hCV260164 rs6754295 T G 167 1373 0.76 0.242.37 0.88 6.39 0.088 dom endpt1 hCV29011391 rs7557067 A G 167 1373 0.760.24 2.34 0.87 6.30 0.094 dom endpt1 hCV29135108 rs6743779 KLF7 C A 1671372 0.32 0.68 1.42 1.04 1.94 0.027 dom endpt1 hCV3242952 rs2000571 A G167 1372 0.22 0.78 1.31 0.96 1.78 0.084 dom endpt1 hCV7537517 rs1501908C G 166 1372 0.64 0.36 2.37 1.25 4.48 0.0083 dom endpt1 hCV7910239rs1541296 FVT1 A G 166 1370 0.66 0.34 1.64 0.95 2.83 0.077 dom endpt1hCV11466848 rs1805419 BAX A G 167 1373 0.28 0.72 1.37 1.01 1.87 0.041dom endpt1 hCV2554721 rs7315519 RPH3A A G 167 1372 0.46 0.54 1.45 1.012.09 0.046 dom endpt1 hCV2762168 rs3939286 T C 167 1371 0.26 0.74 1.471.09 2.00 0.013 dom endpt1 hCV31237961 rs11950562 SLC22A4 A C 167 13710.54 0.46 1.62 1.05 2.49 0.03 dom endpt1 hCV3168675 rs469930 G A 1671371 0.36 0.64 1.31 0.95 1.80 0.097 dom endpt1 hCV3170445 rs272893SLC22A4 T C 167 1373 0.39 0.61 1.62 1.15 2.27 0.0056 dom endpt1hCV610861 rs636887 T C 167 1373 0.57 0.43 1.61 1.02 2.54 0.041 domendpt1 hCV8785824 rs1412426 A C 167 1369 0.33 0.67 1.45 1.06 1.98 0.021dom endpt1 hCV8785827 rs992969 IL33 A G 167 1371 0.26 0.74 1.49 1.102.02 0.01 dom endpt1 hDV70797856 rs17006217 C T 167 1373 0.11 0.89 1.421.01 2.00 0.044 dom endpt1 hCV1026586 rs673548 APOB G A 167 1372 0.770.23 1.47 1.06 2.04 0.02 rec endpt1 hCV11568668 rs1317538 KCNQ5 A G 1661374 0.48 0.52 1.34 0.96 1.87 0.084 rec endpt1 hCV1489995 rs4013819LOC392281 G C 167 1372 0.37 0.63 1.51 1.04 2.20 0.032 rec endpt1hCV1948599 rs504527 CSMD2 C A 167 1370 0.51 0.49 1.44 1.04 1.99 0.03 recendpt1 hCV601962 rs544543 ZNF568 G A 167 1371 0.38 0.62 1.44 0.98 2.110.066 rec endpt1 hCV601961 rs568654 ZNF568 A G 167 1373 0.38 0.62 1.460.99 2.14 0.055 rec endpt1 hCV8369472 rs1447351 MTNR1B G A 167 1373 0.530.47 1.44 1.05 1.98 0.023 rec endpt1 hCV461035 rs7746448 T C 167 13730.60 0.40 1.30 0.96 1.77 0.094 rec endpt1 hCV30606396 rs10438978 T C 1671372 0.17 0.83 1.35 0.98 1.87 0.064 het endpt1 hCV22303 rs4552916 G A167 1373 0.22 0.78 1.32 0.96 1.81 0.087 het endpt1 hCV11856381 rs2197089A G 148 1371 0.55 0.45 1.70 1.05 2.75 0.031 dom rmi hCV15954645rs2954029 A T 148 1371 0.53 0.47 0.70 0.47 1.03 0.072 rec rmihCV28960526 rs6853079 TSPAN5 A T 148 1374 0.78 0.22 1.36 0.96 1.91 0.082rec rmi hCV29480044 rs10516433 TSPAN5 C T 148 1375 0.78 0.22 1.35 0.961.91 0.083 rec rmi hCV29684678 rs10486788 C G 147 1370 0.28 0.72 0.460.20 1.04 0.063 rec rmi hCV30454150 rs10516434 TSPAN5 C T 148 1373 0.780.22 1.34 0.95 1.89 0.09 rec rmi hCV30136303 rs6914527 G C 148 1373 0.600.40 1.42 1.02 1.96 0.036 rec rmi hCV2195496 rs4982795 C T 147 1370 0.440.56 0.69 0.48 1.00 0.05 het rmi hCV2948766 rs4684343 CNTN4 G A 147 13700.58 0.42 1.62 0.97 2.69 0.064 het rmi hCV1253630 rs2071307 ELN A G 1621371 0.41 0.59 0.71 0.522 0.977 0.0354 dom endpt1 hCV15746640 rs41271951CTSS G A 165 1379 0.08 0.92 0.55 0.322 0.932 0.0263 dom endpt1hCV16044337 rs2569491 KLK14 A G 164 1373 0.31 0.69 1.35 0.989 1.8460.0587 dom endpt1 hCV16179493 rs2108622 CYP4F2 T C 165 1379 0.31 0.690.76 0.559 1.032 0.0788 dom endpt1 hCV1647371 rs3025000 VEGFA T C 1611354 0.33 0.67 0.7 0.51 0.949 0.0218 dom endpt1 hCV1843175 rs3745535KLK10 A C 165 1378 0.36 0.64 1.4 1.016 1.921 0.0394 dom endpt1hCV2230606 rs13268 FBLN1 G A 164 1380 0.02 0.98 0.35 0.112 1.097 0.0717dom endpt1 hCV2276802 rs381418 GBA C A 164 1380 0.37 0.63 0.72 0.5180.994 0.0459 dom endpt1 hCV2536595 rs704 VTN A G 165 1383 0.47 0.53 1.711.174 2.497 0.0052 dom endpt1 hCV25472673 rs1805081 NPC1 C T 164 13800.39 0.61 1.47 1.048 2.062 0.0257 dom endpt1 hCV25596880 rs4647297 CASP2C G 165 1380 0.06 0.94 0.6 0.335 1.085 0.0914 dom endpt1 hCV25603879rs11542844 SCNN1A T C 165 1376 0.03 0.97 0.43 0.176 1.046 0.0628 domendpt1 hCV25610819 rs8176740 T A 165 1374 0.23 0.77 0.76 0.556 1.0510.0988 dom endpt1 hCV25614016 rs7607759 CAPN10 G A 165 1379 0.16 0.840.63 0.436 0.92 0.0164 dom endpt1 hCV25617571 rs2232580 LBP T C 165 13820.08 0.92 1.58 1.077 2.311 0.0191 dom endpt1 hCV25629396 rs3729823 MYH7C G 164 1378 0.01 0.99 0.16 0.023 1.163 0.0705 dom endpt1 hCV25631989rs1135983 ATF6 T C 158 1346 0.08 0.92 0.5 0.286 0.89 0.0182 dom endpt1hCV25644901 ITGA9 G A 165 1379 0.05 0.95 1.93 1.272 2.939 0.002 domendpt1 hCV25926178 rs12882130 MARK3 G C 161 1352 0.38 0.62 1.45 1.0412.029 0.0281 dom endpt1 hCV25926771 rs4906321 MARK3 C T 161 1350 0.310.69 1.57 1.116 2.203 0.0094 dom endpt1 hCV25927605 HLA-DPA1 T C 1651375 0.03 0.97 0.3 0.094 0.927 0.0366 dom endpt1 hCV25941408 rs28497577MYLK T G 163 1381 0.10 0.90 1.44 1.003 2.074 0.048 dom endpt1 hCV2633049rs2302006 CCL24 G T 164 1378 0.20 0.81 0.7 0.498 0.98 0.038 dom endpt1hCV2658421 rs3176975 APOH A C 164 1376 0.23 0.77 1.35 0.995 1.836 0.0539dom endpt1 hCV2741051 rs2230806 ABCA1 T C 165 1382 0.28 0.72 0.65 0.4710.884 0.0064 dom endpt1 hCV2741083 rs4149313 ABCA1 C T 165 1381 0.130.87 0.54 0.349 0.842 0.0064 dom endpt1 hCV2983035 rs9527026 KL A G 1631377 0.15 0.85 1.34 0.968 1.865 0.0771 dom endpt1 hCV2983036 rs9527025KL C G 165 1376 0.15 0.85 1.32 0.952 1.83 0.096 dom endpt1 hCV3026189rs11739136 KCNIP1 T C 165 1383 0.10 0.90 0.69 0.442 1.067 0.095 domendpt1 hCV435368 rs2812 PECAM1 T C 164 1380 0.47 0.53 1.61 1.106 2.3530.013 dom endpt1 hCV529706 rs428785 ADAMTS1 C G 164 1375 0.24 0.76 1.421.043 1.923 0.026 dom endpt1 hCV529710 rs402007 ADAMTS1 C G 165 13820.24 0.76 1.42 1.05 1.933 0.023 dom endpt1 hCV5478 rs1800574 TCF1 T C165 1382 0.03 0.97 0.38 0.142 1.032 0.0578 dom endpt1 hCV7499212rs1800127 LRP1 T C 165 1379 0.02 0.98 1.87 1.081 3.232 0.0252 dom endpt1hCV7514870 rs1041981 LTA A C 165 1381 0.33 0.67 1.32 0.968 1.808 0.0791dom endpt1 hCV7577801 rs11876 SLC9A3R2 T C 165 1374 0.22 0.78 0.66 0.4750.93 0.017 dom endpt1 hCV783184 rs510335 T G 164 1379 0.12 0.88 0.690.459 1.048 0.0821 dom endpt1 hCV7900503 rs3732379 CX3CR1 T C 165 13810.28 0.72 0.72 0.524 0.975 0.034 dom endpt1 hCV8718197 rs1050998 CXCL16G A 165 1383 0.44 0.56 0.71 0.519 0.969 0.0311 dom endpt1 hCV8784787rs688976 A C 165 1381 0.23 0.77 0.76 0.552 1.044 0.0897 dom endpt1hCV8901525 rs861539 KLC1 A G 161 1352 0.37 0.63 0.73 0.534 0.991 0.0439dom endpt1 hCV8921288 rs1060621 GAPDH C A 158 1347 0.20 0.80 1.6 1.1692.186 0.0033 dom endpt1 hCV9077561 rs1801274 FCGR2A G A 165 1381 0.500.50 1.47 1 2.164 0.0499 dom endpt1 hCV2741051 rs2230806 ABCA1 T C 1651382 0.28 0.72 0.65 0.471 0.884 0.0064 dom endpt1 hCV435368 rs2812PECAM1 T C 164 1380 0.47 0.53 1.61 1.106 2.353 0.013 dom endpt1hCV8921288 rs1060621 GAPDH C A 158 1347 0.20 0.80 1.6 1.169 2.186 0.0033dom endpt1 hCV11689916 A T 158 1314 0.48 0.52 1.33 0.963 1.849 0.0827rec endpt1 hCV12020339 rs4531 DBH T G 165 1374 0.08 0.92 2.92 0.93 9.1350.0663 rec endpt1 hCV1243283 rs1716 ITGAE A G 165 1379 0.33 0.67 1.571.012 2.444 0.0442 rec endpt1 hCV1552894 rs434473 ALOX12 G A 165 13770.42 0.58 1.49 1.05 2.104 0.0254 rec endpt1 hCV1552900 rs1126667 ALOX12A G 165 1379 0.42 0.58 1.48 1.047 2.098 0.0265 rec endpt1 hCV15851335rs17610395 CPT1A T C 164 1379 0.07 0.93 4.44 1.101 17.895 0.0362 recendpt1 hCV15954277 rs2236379 PRKCQ A G 165 1383 0.26 0.74 0.24 0.0760.75 0.0141 rec endpt1 hCV16173091 rs2241883 FABP1 C T 165 1381 0.320.68 0.53 0.282 1.013 0.0546 rec endpt1 hCV1741111 rs1764391 C1orf212 TC 165 1380 0.30 0.70 0.46 0.203 1.034 0.0602 rec endpt1 hCV2143205rs9666607 CD44 A G 165 1383 0.32 0.68 0.55 0.282 1.08 0.0828 rec endpt1hCV22274761 rs11575194 IGFBP5 A G 165 1378 0.04 0.96 16.7 2.327 119.750.0051 rec endpt1 hCV2503034 rs1132356 BAIAP3 A C 164 1372 0.11 0.893.54 1.13 11.098 0.03 rec endpt1 hCV2531086 rs10406069 CD22 A G 165 13790.21 0.79 0.31 0.076 1.232 0.0955 rec endpt1 hCV25473098 rs2241883 FABP1G A 163 1371 0.31 0.69 0.59 0.319 1.084 0.0889 rec endpt1 hCV25610774rs8176748 T C 165 1382 0.23 0.77 0.23 0.056 0.918 0.0375 rec endpt1hCV25637309 rs3204849 CCRL2 A T 165 1378 0.39 0.61 0.47 0.278 0.8050.0057 rec endpt1 hCV25651174 rs9277356 HLA-DPB1 G A 165 1375 0.30 0.700.46 0.216 0.979 0.044 rec endpt1 hCV2769554 rs1805010 IL4R G A 165 13780.46 0.54 0.51 0.324 0.81 0.0042 rec endpt1 hCV370782 rs9841174 SERPINI2C T 165 1376 0.38 0.62 0.54 0.319 0.924 0.0243 rec endpt1 hCV549926rs1057141 Tap1or C T 165 1376 0.16 0.84 2.05 1.006 4.164 0.0481 recendpt1 hCV7490135 rs1805082 NPC1 C T 165 1376 0.47 0.53 1.38 0.981 1.9290.0645 rec endpt1 hCV8804621 rs1390938 SLC18A1 A G 164 1376 0.25 0.750.38 0.141 1.021 0.0551 rec endpt1 hCV8851065 rs9277343 HLA-DPA1 G C 1651383 0.28 0.72 0.51 0.24 1.093 0.0836 rec endpt1 hCV9604851 rs1805002CCKBR A G 165 1380 0.05 0.95 5.46 1.742 17.11 0.0036 rec endpt1hCV997884 rs512770 A G 164 1370 0.20 0.80 0.24 0.059 0.957 0.0432 recendpt1 hCV3135085 rs10795446 CUBN G T 164 1370 0.33 0.67 0.74 0.5331.034 0.0781 het endpt1 hCV3215409 rs267561 ITGA9 G A 165 1381 0.42 0.581.48 0.955 2.28 0.0797 hom endpt1 hCV7494810 rs1058587 GDF15 G C 1651379 0.25 0.75 1.35 0.987 1.844 0.0608 het endpt1 hCV783138 rs6046 F10 AG 163 1377 0.11 0.89 0.66 0.417 1.045 0.0762 het endpt1 hCV795442rs375947 IL12RB1 G A 164 1381 0.32 0.68 0.74 0.535 1.032 0.0765 hetendpt1 hCV818008 rs5918 ITGB3 C T 165 1381 0.15 0.85 1.33 0.956 1.8390.0914 het endpt1

1. A method of determining whether a human has an altered risk forcardiovascular disease (CVD), comprising testing nucleic acid from saidhuman for the presence or absence of a polymorphism selected from thegroup consisting of the polymorphisms as represented by position 101 ofany one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 orits complement, wherein said polymorphism indicates said human has analtered risk for CVD.
 2. The method of claim 1, wherein said CVD iscoronary heart disease (CHD).
 3. The method of claim 2, wherein said CHDis myocardial infarction.
 4. The method of claim 1, wherein saidpolymorphism is in the GOSR2 gene and wherein said CVD is hypertension.5. The method of claim 1, wherein said altered risk is an increasedrisk.
 6. The method of claim 1, wherein said altered risk is a decreasedrisk.
 7. The method of claim 1, wherein said nucleic acid is a nucleicacid extract from a biological sample from said human.
 8. The method ofclaim 7, wherein said biological sample is blood, saliva, or buccalcells.
 9. The method of claim 7, further comprising preparing saidnucleic acid extract from said biological sample prior to said testingstep.
 10. The method of claim 9, further comprising obtaining saidbiological sample from said human prior to said preparing step.
 11. Themethod of claim 1, wherein said testing step comprises nucleic acidamplification.
 12. The method of claim 11, wherein said nucleic acidamplification is carried out by polymerase chain reaction.
 13. Themethod of claim 1, further comprising correlating the presence orabsence of said polymorphism with an altered risk for CVD.
 14. Themethod of claim 13, wherein said correlating step is performed bycomputer software.
 15. The method of claim 1, wherein said testing isperformed using sequencing, 5′ nuclease digestion, molecular beaconassay, oligonucleotide ligation assay, size analysis, single-strandedconformation polymorphism analysis, or denaturing gradient gelelectrophoresis (DGGE).
 16. The method of claim 1, wherein said testingis performed using an allele-specific method.
 17. The method of claim16, wherein said allele-specific method is allele-specific probehybridization, allele-specific primer extension, or allele-specificamplification.
 18. The method of claim 17, wherein said method isperformed using an allele-specific primer provided in Table
 5. 19. Themethod of claim 1 which is an automated method.
 20. The method of claim1, further comprising correlating the presence of said polymorphism withsaid human's responsiveness to a therapeutic agent.
 21. The method ofclaim 20, wherein said therapeutic agent comprises an HMG-CoA reductaseinhibitor.
 22. The method of claim 21, wherein said polymorphism isselected from the group consisting of the polymorphisms provided inTable
 22. 23. The method of claim 20, wherein said therapeutic agent isevaluated in a clinical trial.
 24. The method of claim 1, furthercomprising the step of selecting said human for inclusion in a clinicaltrial of a therapeutic agent or assigning said human to a group within aclinical trial.
 25. The method of claim 24, wherein said therapeuticagent comprises an HMG-CoA reductase inhibitor.
 26. A method ofdetermining whether a human will respond to an HMG-CoA reductaseinhibitor for reducing risk for cardiovascular disease (CVD), comprisingtesting nucleic acid from said human for the presence or absence of apolymorphism selected from the group consisting of the polymorphismsprovided in Table
 21. 27. The method of claim 26, further comprisingadministering said HMG-CoA reductase inhibitor to said human.
 28. Themethod of claim 26, further comprising the step of selecting said humanfor inclusion in a clinical trial of a therapeutic agent or assigningsaid human to a group within a clinical trial.
 29. A method for reducingrisk of cardiovascular disease (CVD) in a human, comprisingadministering to said human an effective amount of a therapeutic agent,said human having been identified as having an increased risk for CVDdue to the presence or absence of a polymorphism selected from the groupconsisting of the polymorphisms as represented by position 101 of anyone of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or itscomplement.
 30. The method of claim 29, wherein said method comprisestesting nucleic acid from said human for the presence or absence of saidpolymorphism.
 31. The method of claim 29, wherein said CVD is coronaryheart disease (CHD).
 32. The method of claim 31, wherein said CHD ismyocardial infarction.
 33. The method of claim 29, wherein saidtherapeutic agent comprises an HMG-CoA reductase inhibitor.
 34. A methodfor reducing risk of cardiovascular disease (CVD) in a human, comprisingadministering to said human an effective amount of an HMG-CoA reductaseinhibitor, said human having been predicted to respond to said HMG-CoAreductase inhibitor for reducing said risk of CVD due to the presence orabsence of a polymorphism selected from the group consisting of thepolymorphisms provided in Table
 21. 35. The method of claim 34, whereinsaid method comprises testing nucleic acid from said human for thepresence or absence of said polymorphism.
 36. The method of claim 34,wherein said CVD is coronary heart disease (CHD).
 37. The method ofclaim 36, wherein said CHD is myocardial infarction.
 38. A method ofidentifying a human having an increased risk for cardiovascular disease(CVD), comprising testing a nucleic acid sample from said human for thepresence or absence of a first polymorphism which is in linkagedisequilibrium with a second polymorphism, wherein said secondpolymorphism is a polymorphism selected from the group consisting of thepolymorphisms as represented by position 101 of any one of thenucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement,and wherein said first polymorphism identifies said human as having anincreased risk for CVD.
 39. The method of claim 38, wherein said linkagedisequilibrium is r²=1.
 40. The method of claim 38, wherein said firstpolymorphism is selected from the group consisting of the polymorphismsprovided in Table
 6. 41. A kit for determining whether a human has analtered risk for cardiovascular disease (CVD), wherein said kitcomprises at least one container and at least one oligonucleotide storedin said container, wherein said oligonucleotide is capable of detectingthe presence or absence of a polymorphism selected from the groupconsisting of the polymorphisms as represented by position 101 of anyone of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or itscomplement.
 42. The kit of claim 41, wherein said oligonucleotideselectively hybridizes to said nucleic acid in the presence of saidpolymorphism and does not hybridize to said nucleic acid in the absenceof said polymorphism.
 43. The method of claim 41, wherein saidoligonucleotide comprises at least one allele-specific primer providedin Table
 5. 44. A method of determining whether a human will benefitfrom hormone replacement therapy, comprising testing nucleic acid fromsaid human for the presence of absence of LPA polymorphism rs3798220,wherein C or its complement at said polymorphism indicates said humanwill benefit from hormone replacement therapy.
 45. The method of claim44, further comprising administering hormone replacement therapy to saidhuman.